Hydroxynaphthyridinone carboxamides useful as hiv integrase inhibitors

ABSTRACT

Hydroxynaphthyridinone carboxamides of formula:  
                 
 
are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein L, R 1a , R 1b , R 1c , R 2a , R 2b , R 3 , R 4 , and R 5  are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

This application claims the benefit of U.S. Provisional Application No.60/349,775, filed Jan. 17, 2002, the disclosure of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamides andpharmaceutically acceptable salts thereof, their synthesis, and theiruse as inhibitors of the HIV integrase enzyme. The compounds of thepresent invention and their pharmaceutically acceptable salts are usefulfor preventing or treating infection by HIV and for treating, delayingthe onset of, or preventing AIDS.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.This virus was previously known as LAV, HTLV-III, or ARV. A commonfeature of retrovirus replication is the insertion by virally-encodedintegrase of proviral DNA into the host cell genome, a required step inHIV replication in human T-lymphoid and monocytoid cells. Integration isbelieved to be mediated by integrase in three steps: assembly of astable nucleoprotein complex with viral DNA sequences; cleavage of twonucleotides from the 3′termini of the linear proviral DNA; covalentjoining of the recessed 3′OH termini of the proviral DNA at a staggeredcut made at the host target site. The fourth step in the process, repairsynthesis of the resultant gap, may be accomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame [Ratner et al., Nature 1985, 313: 277]. Amino acidsequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Toh et al., EMBOJ. 1985, 4: 1267; Power et al., Science 1986, 231: 1567; Pearl et al.,Nature 1987, 329: 351]. All three enzymes have been shown to beessential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhbitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication. The inhibition ofintegrase in vitro and of HIV replication in cells is a direct result ofinhibiting the strand transfer reaction catalyzed by the recombinantintegrase in vitro in HIV infected cells. The particular advantage ofthe present invention is highly specific inhibition of HIV integrase andHIV replication.

The following references are of interest as background:

Hart, J. Chem. Soc. 1954, 1879-1882 describes the amination,hydroxylation, oxidation and chlorination of 1,5-naphthyridine.

Oakes et al., J. Chem. Soc. 1958, 204-208 discloses the preparation ofcertain 2,4-disubstituted 1,5-naphthyridines including2,4-dihydroxy-1,5-naphthyridine.

McCaustland et al., J. Heterocyclic Chem. 1970, 7: 467-473 discloses thepreparation of 7-chloro-2,4-dihydroxy-1,5-naphthyridine.

Buckle et al., J. Med. Chem. 1975, 18: 726-732 discloses the preparationof 4-hydroxy-3-nitro-1,5-naphthyridin-2(1H)-one by direct nitration ofthe corresponding ketoamide.

Dunn, Z. Chem. 1990, 30: 20-21 discloses the preparation of4-amino-3-ethoxycarbonyl-1,5-naphthyridin-2(1H)-one by heating diethylmalonate, sodium ethoxide, and 3-amino-2-cyanopyridine under reflux.

Chen et al., J. Heterocyclic Chem. 1993, 30: 909-912 discloses thepreparation of 4-hydroxy-3-(o-methoxyphenyl)-1,5-naphthyridin-2(1H)-oneby refluxing the ethyl ester of3-(o-methoxybenzylcarbonylamino)pyridine-2-carboxylic acid with sodiumethoxide in benzene.

Zografos et al., J. Org. Chem. 2001, 66: 4413-4415 discloses thepreparation of certain 4-hydroxy-1,8-naphthyridin-2-ones by reacting apyrido[2,3-d)[3,1]oxazin4-one with the anion of a beta-ketoester formedby treatment with t-BuOK.

U.S. Pat. No. 4,996,213 discloses certain4-amino-3-carboxy-1,5-naphthyridine derivatives. The derivatives aredisclosed to have nervous system affecting properties.

U.S. Pat. No. 5,294,620 discloses certain 1,6-naphthyridin-2-onederivatives having angiotensin D antagonist activity.

WO 96/11198 and WO 96/11199 disclose certain4-hydroxy-1,8-naphthyridin-2-one derivatives

WO 95/00511 discloses certain 4-(phenyl- or pyridyl- orpyriridinyl-amino)-1,5-naphthyridine derivatives. The derivatives aredisclosed to be anti-rheumatic agents.

WO 02/30930 (Publication of International Application No. PCT/US01/31456, filed Oct. 9, 2001) discloses certain8-hydroxy-1,6-naphthyridine-7-carboxamides which are HIV integraseinhibitors useful, inter alia, for treating HIV infection and AIDS.

SUMMARY OF THE INVENTION

The present invention is directed to novel hydroxynaphthyridinonecarboxamides. These compounds are useful in the inhibition of HIVintegrase, the prevention of infection by HIV, the treatment ofinfection by HIV and in the prevention, treatment, and delay in theonset of AIDS and/or ARC, either as compounds or their pharmaceuticallyacceptable salts, or as pharmaceutical composition ingredients, whetheror not in combination with other HIV/AIDS antivirals, anti-infectives,immunomodulators, antibiotics or vaccines. More particularly, thepresent invention includes a compound of Formula (I):

wherein L is a linker connecting the carbon atom of the phenyl ring tothe nitrogen of the —NH— moiety, wherein L is

-   -   (i) a single bond,    -   (ii) —(C₁₋₆ alkyl)-, which is optionally substituted with        —C(═O)N(R^(a)R^(b)),    -   (iii) —(C₀₋₃ alkyl)-C═C—(C₁₋₃ alkyl)-,    -   (iv) —(CO₀₋₃ alkyl)-C≡C—(C₁₃₋ alkyl)-, or    -   (v) —(C₀₋₆ alkyl)-(C₃₋₆ cycloalkyl)-(C₀₋₆ alkyl)-;    -   R^(1a), R^(1b), and R^(1c) are each independently —H, halogen,        —C₁₋₆ alkyl, or —C₁₋₆ haloalkyl;    -   R^(2a) and R^(2b) are each independently:        -   (1) —H,        -   (2) —C₁₋₆ alkyl, optionally substituted with one or more            substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1            to 4, or 1 to 3, or 1 or 2 substituents; or is optionally            mono-substituted) each of which is independently halogen,            —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂,            —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a),            —OCO₂R^(a), —OCO₂R^(a), —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)),            —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b),            or —N(R^(a))SO₂N(R^(a)R^(b)),        -   (3) —C₁₋₆ alkyl substituted with one substituent which is            -C₃₋₈ cycloalkyl, aryl, or heteroaryl, wherein:            -   (a) the cycloalkyl is optionally substituted with one or                more substituents (e.g., optionally from 1 to 6, or 1 to                5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is                optionally mono-substituted) each of which is                independently halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆                alkyl-O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,                —O—C₁₋₆ haloalkyl, or phenyl;            -   (b) the aryl is an aromatic carbocyclic ring or an                aromatic carbocyclic fused ring system, wherein the aryl                is optionally substituted with one or more substituents                (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or                1 to 3, or 1 or 2 substituents; or is optionally                mono-substituted) each of which is independently                halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl,                —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN,                —NO₂, —N(R^(a)R^(b)), —C₁₋₆ alkyl-N(R^(a)R^(b)),                —C(═O)N(R^(a)R^(b)), —C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),                —C(═O)R^(a), —C₁₋₆ alkyl-C(═O)R^(a), —CO₂R^(a), —C₁₋₆                alkyl-CO₂R^(a), —OCO₂R^(a), —C₁₋₆ alkyl-OCO₂R^(a),                —S(O)_(n)R^(a), —C₁₋₆ alkyl-S(O)_(n)R^(a),                —SO₂N(R^(a)R^(b)), —C₁₋₆ alkyl-SO₂N(R^(a)R^(b)),                —N(R^(a))SO₂R_(b), —C₁₋₆ alkyl-N(R^(a))SO₂R^(b),                —N(R^(a))C(═O)R^(b), —C₁₋₆ alkyl-N(R^(a))C(═O)R^(b),                —N(R^(a))CO₂R^(b), —C₁₋₆ alkyl-N(R^(a))CO₂R^(b),                —N(R^(a))SO₂N(R^(a)R^(b)), —C₁₋₆                alkyl-N(R^(a))SO₂N(R^(a)R^(b)), phenyl, —C₁₋₆                alkyl-phenyl, —O-phenyl, —C₁₋₆ alkyl-O-phenyl, HetA, or                —C₁₋₆ alkyl-HetA; wherein each HetA is a 5- or                6-membered heteroaromatic ring containing from 1 to 4                heteroatoms independently selected from N, O and S,                wherein the heteroaromatic ring is optionally fused with                a benzene ring; and wherein each HetA is optionally                substituted with one or more substituents (e.g.,                optionally from 1 to 4, or 1 to 3, or 1 or 2                substituents; or is optionally mono-substituted) each of                which is independently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl,                —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo, or —CO₂R^(a); and            -   (c) the heteroaryl is a 5- or 6-membered heteraromatic                ring containing from 1 to 4 heteroatoms or a 9- or                10-membered bicyclic heteroaromatic ring system                containing from 1 to 6 heteroatoms, wherein the                heteroatoms in the heteroaryl are independently selected                from N, O and S; and wherein the heteroaryl is                optionally substituted with one or more substituents                (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or                1 to 3, or 1 or 2 substituents; or is optionally                mono-substituted) each of which is independently                halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl,                —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,                —N(R^(a)R^(b)), —C₁₋₆ alkyl-N(R^(a)R^(b)),                —C(═O)N(R^(a)R^(b)), —C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),                —C(═O)R^(a), —C₁₋₆ alkyl-C(═O)R^(a), —CO₂R^(a), —C₁₋₆                alkyl-CO₂R^(a), —OCO₂R^(a), —C₁₋₆ alkyl-OCO₂R^(a),                —S(O)_(n)R^(a), —C₁₋₆ alkyl-S(O)_(n)R^(a),                —SO₂N(R^(a)R^(b)), —C₁₋₆ alkyl-SO₂N(R^(a)R^(b)),                —N(R^(a))SO₂R^(b), —C₁₋₆ alkyl-N(R^(a))SO₂R^(b),                —N(R^(a))C(═O)R^(b), —C₁₋₆ alkyl-N(R^(a))C(═O)R^(b),                —N(R^(a))CO₂R^(b), —C₁₋₆ alkyl-N(R^(a))CO₂R^(b), phenyl,                —C₁₋₆ alkyl-phenyl, or oxo;        -   (4) —O—C₁₋₆ alkyl, optionally substituted with one or more            substituents (e.g., optionally from 1 to 4, or 1 to 3, or 1            or 2 substituents; or is optionally mono-substituted) each            of which is independently halogen, —OH, —O—C₁₋₆ alkyl,            —O—C₁₋₆ haloalkyl, —S(O)_(n)R^(a), —N(R^(a))—CO₂R^(b), or            —C(═O)N(R^(a)R^(b)),        -   (5) —OH,        -   (6) halo,        -   (7) —NO₂,        -   (8) —CN,        -   (9) —C(═O)R^(a),        -   (10) —CO₂R^(a),        -   (11) —S(O)_(n)R^(a),        -   (12) —SO₂N(R^(a)R^(b)),        -   (13) —N(R^(a)R^(b)),        -   (14) —C(═O)N(R^(a)R^(b)),        -   (15) —N(R^(a))SO₂R^(b),        -   (16) —OC(═O)N(R^(a)R^(b)),        -   (17) —N(R^(a))C(═O)NR^(a)R^(b)),        -   (18) —N(R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),        -   (19) —N(R^(a))-C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),        -   (20) —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),        -   (21) —OCO₂R^(a),        -   (22) —N(R^(a))—SO₂N(R^(a)R^(b)),        -   (23) —N(R^(a))—SO₂—C₁₋₆ alkyl-N(R^(a)R^(b)),        -   (24) —N(R^(a))C(═O)R^(b),        -   (25) —N(R^(a))CO₂R^(b),        -   (26) —S—C₁₋₆ alkyl-C(═O)N(R_(a)R_(b)), or        -   (27) —N(SO₂R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b));    -   R³ is        -   (1) —H,        -   (2) —C₁₋₆ alkyl, optionally substituted with one or more            substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1            to 4, or 1 to 3, or 1 or 2 substituents; or is optionally            mono-substituted) each of which is independently halogen,            —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂,            —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),            N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆            alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C(═O)—C₁₋₆            alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),            —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a), —S(O)_(n)R^(a),            —SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂N(R^(a)R^(b)),            —N(R^(a))—SO₂—C₁₋₆ alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),            —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or -G-C₁₋₆            alkyl-C(═O)N(R^(a)R^(b)) wherein G is O or S or N(SO₂R^(a)),            -   with the proviso that none of the following substituents                is attached to the carbon in the —C₁₋₆ alkyl group that                is attached to (i.e., alpha to) the ring nitrogen: —OH,                —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —NO₂, —N(R^(a)R^(b)),                —OC(═O)N(R^(a)R^(b)), —N(R^(a))C(═O)N(R^(a)R^(b)),                —N(R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),                —N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),                —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —OCO₂R^(a),                —N(R^(a))—SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂—C₁₋₆                alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),                —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or -G-C₁₋₆                alkyl-C(═O)N(R^(a)R^(b)) wherein G is O or N(SO₂R^(a)),        -   (3) —C₁₋₆ alkyl substituted with one of:            -   (i) —R^(k),            -   (ii) —S(O)_(n)—R^(k),            -   (iii) —S(O)_(n)—C₁₋₆ alkyl-R^(k),            -   (iv) —C(═O)—R^(k),            -   (v) —C(═O)—C₁₋₆ alkyl-R^(k),            -   (vi) —C(═O)N(R^(a))—R^(k), or            -   (vii) —C(═O)N(R^(a))—C₁₋₆ alkyl-R^(k),        -   (4) —C₂₋₆ alkyl substituted with one of:            -   (i) —O—R^(k),            -   (ii) —O—C₁₋₆ alkyl-R^(k),            -   (iii) —N(R^(a))—R^(k),            -   (iv) —N(R^(a))—C₁₋₆ alkyl-R_(k),            -   (v) —N(R^(a))C(═O)—R^(k),            -   (vi) —N(R^(a))C(═O)—C₁₋₆ alkyl-R^(k),            -   with the proviso that the substituent is not attached to                the carbon in the —C₂₋₆ alkyl group that is attached to                (i.e., alpha to) the ring nitrogen,        -   (5) —S(O)_(n)R^(a),        -   (6) —SO₂N(R^(a)R^(b)),        -   (7) —C₂₋₆ alkenyl, optionally substituted with one            substituent which is —C(═O)—N(R^(a)R^(b)) or —R^(k),        -   (8) —C₂₋₅ alkynyl, optionally substituted with one            substituent which is —CH₂N(R^(a)R^(b)), —CH₂OR^(a), or            —R^(k),        -   (9) —R^(k),        -   (10) —S(O)_(n)—C₁₋₆ alkyl-R^(k),        -   (11) —N(R^(a))C(═O)—R^(k), or        -   (12) —N(R^(a))C(═O)—C₁₋₆ alkyl-R^(k);    -   each of R⁴ and R⁵ is independently        -   (1) —H,        -   (2) —C₁₋₆ alkyl, optionally substituted with one or more            substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1            to 4, or 1 to 3, or 1 or 2 substituents; or is optionally            mono-substituted) each of which is independently halogen,            —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂,            —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),            —N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆            alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C(═O)—C₁₋₆            alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),            —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a), —S(O)_(n)R^(a),            —SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂N(R^(a)R^(b)),            —N(R^(a))—SO₂—C₁₋₆ alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),            —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or -G-C₁₋₆            alkyl-C(═O)N(R^(a)R^(b)) wherein G is O or S or N(SO₂R^(a)),        -   (3) —SO₂N(R^(a)R^(b)), or        -   (4) —C₁₋₆ alkyl-R^(m);    -   each R^(a) and R^(b) is independently —H, —C₁₋₆ alkyl, or —C₃₋₈        cycloalkyl;    -   R^(k) is a carbocycle or a heterocycle;    -   each R^(m) is independently a carbocycle or a heterocycle;    -   each carbocycle is independently (i) a C₃ to C₈ monocyclic,        saturated or unsaturated ring, (ii) a C₇ to C₁₂ bicyclic ring        system, or (iii) a C₁₁ to C₁₆ tricyclic ring system, wherein        each ring in (ii) or (iii) is independent of or fused to the        other ring or rings and each ring is saturated or unsaturated;        wherein the carbocycle is optionally substituted with one or        more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1        to 4, or 1 to 3, or 1 or 2 substituents; or is optionally        mono-substituted) each of which is independently        -   (1) halogen,        -   (2) —OH,        -   (3) —C₁₋₆ alkyl, optionally substituted with one or more            substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1            to 4, or 1 to 3, or 1 or 2 substituents; or is optionally            mono-substituted) each of which is independently —OH,            —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),            —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a),            —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b),            —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b),            phenyl, —O-phenyl, or HetB,        -   (4) —C₁₋₆ haloalkyl,        -   (5) —O—C₁₋₆ alkyl,        -   (6) —O—C₁₋₆ haloalkyl,        -   (7) —CN,        -   (8) —NO₂,        -   (9) —N(R^(a)R^(b)),        -   (10) —C(═O)N(R^(a)R^(b)),        -   (1 1) —C(═O)R^(a),        -   (12) —CO₂R^(a),        -   (13) —OCO₂R^(a),        -   (14) —S(O)_(n)R^(a),        -   (15) —N(R^(a))SO₂R^(b),        -   (16) —SO₂N(R^(a)R^(b)),        -   (17) —N(R^(a))C(═O)R^(b),        -   (18) —N(R^(a))CO₂R^(b),        -   (19) phenyl,        -   (20) —O-phenyl, or        -   (21) HetB,            -   wherein each HetB is independently a 5- or 6-membered                heteroaromatic ring containing from 1 to 4 heteroatoms                independently selected from N, O and S, wherein the                heteroaromatic ring is optionally fused with a benzene                ring; and wherein each HetB is optionally substituted                with one or more substituents (e.g., optionally from 1                to 4, or 1 to 3, or 1 or 2 substituents; or is                optionally mono-substituted) each of which is                independently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆                alkyl, —O—C₁₋₆ haloalkyl, oxo, or —CO₂R^(a);    -   each heterocycle is independently (i) a 4- to 8-membered,        saturated or unsaturated monocyclic ring, (ii) a 7- to        12-membered bicyclic ring system, or (iii) an 11 to 16-membered        tricyclic ring system; wherein each ring in (ii) or (iii) is        independent of or fused to the other ring or rings and each ring        is saturated or unsaturated; the monocyclic ring, bicyclic ring        system, or tricyclic ring system contains from 1 to 6        heteroatoms independently selected from N, O and S; and wherein        any one or more of the nitrogen and sulfur heteroatoms is        optionally oxidized, and any one or more of the nitrogen        heteroatoms is optionally quaternized; wherein the heterocycle        is optionally substituted with one or more substituents (e.g.,        optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or        2 substituents; or is optionally mono-substituted) each of which        is independently        -   (1) halogen,        -   (2) —OH,        -   (3) —C₁₋₆ alkyl, optionally substituted with one or more            substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1            to 4, or 1 to 3, or 1 or 2 substituents; or is optionally            mono-substituted) each of which is independently —OH,            —O—C₁₋₆ alkyl, —CN, —NO₂, —N(R^(a)R^(b)),            —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),            —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),            —N(R^(a))CO₂R^(b), phenyl, —O-phenyl, or HetC,        -   (4) —C₁₋₆ haloalkyl,        -   (5) —O—C₁₋₆ alkyl,        -   (6) —O—C₁₋₆ haloalkyl,        -   (7) —CN,        -   (8) —NO₂,        -   (9) —N(R^(a)R^(b)),        -   (10) —C(═O)N(R^(a)R^(b)),        -   (11) —C(═O)R^(a),        -   (12) —CO₂R^(a),        -   (13) —OCO₂R^(a),        -   (14) —S(O)_(n)R^(a),        -   (15) —N(R^(a))SO₂R^(b),        -   (16) —SO₂N(R^(a)R^(b)),        -   (17) —N(R^(a))C(═O)R^(b),        -   (18) —N(R^(a))CO₂R^(b),        -   (19) phenyl,        -   (20) —O-phenyl,        -   (21) HetC, or        -   (22) oxo;            -   wherein each HetC is independently a 5- or 6-membered                heteroaromatic ring containing from 1 to 4 heteroatoms                independently selected from N, O and S, wherein the                heteroaromatic ring is optionally fused with a benzene                ring; and wherein each HetC is optionally substituted                with one or more substituents (e.g., optionally from 1                to 4, or 1 to 3, or 1 or 2 substituents; or is                optionally mono-substituted) each of which is                independently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆                alkyl, —O—C₁₋₆ haloalkyl, oxo, or —CO₂R^(a); and    -   each n is independently an integer equal to 0, 1 or 2;    -   or a pharmaceutically acceptable salt thereof.

The present invention also includes pharmaceutical compositionscontaining a compound of the present invention and methods of preparingsuch pharmaceutical compositions. The present invention further includesmethods of treating AIDS, methods of delaying the onset of AIDS, methodsof preventing AIDS, methods of preventing infection by HIV, and methodsof treating infection by HIV.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the 4-hydroxy-1,5-naphthyridin-2-one3-carboxamiides of Formula (1) above. These compounds andpharmaceutically acceptable salts thereof are HIV integrase inhibitors.

A first embodiment of the present invention is a compound of Formula(I), wherein R^(1a), R^(1b), and R^(1c) are each independently —H,fluoro, chloro, bromo, —C₁₋₄ alkyl, or —CF₃;

-   -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A second embodiment of the present invention is a compound of Formula(I), wherein R^(1a) and R^(1c) are both —H; and R^(1b) is —H, halogen,—C₁₋₆ alkyl, or —C₁₋₆ haloalkyl;

-   -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the second embodiment, R^(1a) and R^(1c) are both —H;and R^(1b) is fluoro, chloro, bromo, —C₁₋₄ alkyl, or —CF₃. In stillanother aspect of the preceding embodiment, R^(1a) and R^(1c) are both—H; and R^(1b) is fluoro.

A third embodiment of the present invention is a compound of Formula(I), wherein one of R^(2a) and R^(2b) is —H, and the other of R^(2a) andR^(2b) is as originally defined above;

-   -   and all other variables are as originally defined above;    -   or a pharmaceutically acceptable salt thereof.

A fourth embodiment of the present invention is a compound of Formula(I), wherein R^(2a) and R^(2b) are each independently:

-   -   (1) —H,    -   (2) —C₁₋₆ alkyl, optionally substituted with from 1 to 5        substituents each of which is independently halogen, —OH,        —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a),        —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),        —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or        —N(R^(a))SO₂N(R^(a)R^(b)), (3) —C₁₋₆ alkyl substituted with one        substituent which is —C₃₋₈ cycloalkyl, aryl, or heteroaryl,        wherein:        -   (a) the cycloalkyl is optionally substituted with from 1 to            5 substituents each of which is independently halogen, —OH,            —C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl,            —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or phenyl;        -   (b) the aryl is an aromatic carbocyclic ring or an aromatic            carbocyclic fused ring system, wherein the aryl is            optionally substituted with from 1 to 5 substituents each of            which is independently halogen, —OH, —C₁₋₄ alkyl, —C₁₋₄            alkyl-O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄            haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)), —C₁₋₄            alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C₁₋₄            alkyl-C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —C₁₋₄            alkyl-C(═O)R^(a), —CO₂R^(a), —C₁₋₄ alkyl-CO₂R^(a),            —OCO₂R^(a), —C₁₋₄ alkyl-OCO₂R^(a), —S(O)_(n)R^(a), —C₁₋₄            alkyl-S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —C₁₋₄            alkyl-SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b), —C₁₋₄            alkyl-N(R^(a))SO₂R^(b), —N(R^(a))C(═O)R^(b), —C₁₋₄            alkyl-N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —C₁₋₄            alkyl-N(R^(a))CO₂R^(b), —N(R^(a))SO₂N(R^(a)R^(b)), —C₁₋₄            alkyl-N(R^(a))SO₂N(R^(a)R^(b)), phenyl, —C₁₋₄ alkyl-phenyl,            —O-phenyl, —C₁₋₄ alkyl-O-phenyl, HetA, or —C₁₋₄ alkyl-HetA;            wherein each HetA is a 5- or 6-membered heteroaromatic ring            containing from 1 to 4 heteroatoms independently selected            from N, O and S, wherein the heteroaromatic ring is            optionally fused with a benzene ring; and wherein each HetA            is optionally substituted with from 1 to 4 substituents each            of which is independently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,            —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, oxo, or —CO₂R^(a); and        -   (c) the heteroaryl is a 5- or 6-membered heteraromatic ring            containing from 1 to 4 heteroatoms or a 9- or 10-membered            bicyclic heteroaromatic ring system containing from 1 to 6            heteroatoms, wherein the heteroatoms in the heteroaryl are            independently selected from N, O and S; and wherein the            heteroaryl is optionally substituted with from 1 to 5            substituents each of which is independently halogen, —OH,            —C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl,            —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —N(R^(a)R^(b)), —C₁₋₄            alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C₁₋₄            alkyl-C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —C₁₋₄            alkyl-C(═O)R^(a), —CO₂R^(a), —C₁₋₄ alkyl-CO₂R^(a),            —OCO₂R^(a), —C₁₋₄ alkyl-OCO₂R^(a), —S(O)_(n)R^(a), —C₁₋₄            alkyl-S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —C₁₋₄            alkyl-SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b), —C₁₋₄            alkyl-N(R^(a))SO₂R^(b), —N(R^(a))C(═O)R^(b), —C₁₋₄            alkyl-N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —C₁₋₄            alkyl-N(R^(a))CO₂R^(b), phenyl, —C₁₋₄ alkyl-phenyl, or oxo;    -   (4) —O—C₁₋₆ alkyl, optionally substituted with from 1 to 5        substituents each of which is independently halogen, —OH,        —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —S(O)_(n)R^(a),        —N(R^(a))—CO₂R^(b), or —C(═O)N(R^(a)R^(b)),    -   (5) —OH,    -   (6) halo,    -   (7) —NO₂,    -   (8) —CN,    -   (9) —C(═O)R^(a),    -   (10) —CO₂R^(a),    -   (11) —S(O)_(n)R^(a),    -   (12) —SO₂N(R^(a)R^(b)),    -   (13) —N(R^(a)R^(b)),    -   (14) —C(═O)N(R^(a)R^(b)),    -   (15) —N(R^(a))SO₂R^(b),    -   (16) —OC(═O)N(R^(a)R^(b)),    -   (17) —N(R^(a))C(═O)N(R^(a)R^(b)),    -   (18) —N(R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),    -   (19) —N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),    -   (20) —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),    -   (21) —OCO₂R^(a),    -   (22) —N(R^(a))—SO₂N(R^(a)R^(b)),    -   (23) —N(R^(a))—SO₂—C₁₋₆ alkyl-N(R^(a)R^(b)),    -   (24) —N(R^(a))C(═O)R^(b),    -   (25) —N(R^(a))CO₂R^(b),    -   (26) —S—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), or    -   (27) —N(SO₂R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b));    -   and all other variables are as originally defined above;    -   or a pharmaceutically acceptable salt thereof.

A fifth embodiment of the present invention is a compound of Formula(I), wherein R^(2a) and R^(2b) are each independently:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl, optionally substituted with 1 or 2 substituents        each of which is independently —OH, —O—C₁₋₄ alkyl, —O—CF₃, —CN,        —NO₂, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R_(a),        —CO₂R^(a), —OCO₂R^(a), —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)),        —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b),    -   (3) —CF₃,    -   (4) —C₁₋₄ alkyl substituted with one of —C₃₋₆ cycloalkyl, aryl,        or heteroaryl, wherein:        -   the cycloalkyl is optionally substituted with 1 or 2            substituents each of which is independently fluoro, chloro,            bromo, —OH, —C₁₋₄ alkyl, —(CH₂)₁₋₂—O—C₁₋₄ alkyl, —CF₃,            —O—C₁₋₄ alkyl, —OCF₃, or phenyl;        -   the aryl is phenyl, naphthyl, anthryl, or phenanthryl;            wherein the aryl is optionally substituted with from 1 to 3            substituents each of which is independently fluoro, chloro,            bromo, —OH, —C₁₋₄ alkyl, —(CH₂)₁₋₂—O—C₁₋₄ alkyl, —CF₃,            —O—C₁₋₄ alkyl, —OCF₃, —CN, —NO₂, —N(R^(a)R^(b)), —C₁₋₄            alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C₁₋₄            alkyl-C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —C₁₋₄            alkyl-C(═O)R^(a), —CO₂R^(a), —C₁₋₄ alkyl-CO₂R^(a),            —OCO₂R^(a), —C₁₋₄ alkyl-OCO₂R^(a), —S(O)_(n)R^(a), —C₁₋₄            alkyl-S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —C₁₋₄            alkyl-SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b), —C₁₋₄            alkyl-N(R^(a))SO₂R^(b), —N(R^(a))C(═O)R^(b), —C₁₋₄            alkyl-N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —C₁₋₄            alkyl-N(R^(a))CO₂R^(b), —N(R^(a))SO₂N(R^(a)R^(b)), —C₁₋₄            alkyl-N(R^(a))SO₂N(R^(a)R^(b)), phenyl, —C₁₋₄ alkyl-phenyl,            —O-phenyl, —C₁₋₄ alkyl-O-phenyl, HetA, or —C₁₋₄ alkyl-HetA;            wherein each HetA is a 5- or 6-membered heteroaromatic ring            containing from 1 to 4 heteroatoms independently selected            from N, O and S, wherein the heteroaromatic ring is            optionally fused with a benzene ring; and wherein each HetA            is optionally substituted with from 1 to 4 substituents each            of which is independently —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl,            —OCF₃, oxo, or —CO₂R^(a); and        -   the heteroaryl is a 5- or 6-membered heteroaromatic ring            containing from 1 to 4 heteroatoms independently selected            from N, O and S; wherein the heteroaryl is optionally            substituted with 1 or 2 substituents each of which is            independently fluoro, chloro, bromo, —OH, —C₁₋₄ alkyl,            —(CH₂)₁₋₂—O—C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃,            —N(R^(a)R^(b)), —C₁₋₄ alkyl-N(R^(a)R^(b)),            —C(═O)N(R^(a)R^(b)), —C₁₋₄ alkyl-C(═O)N(R^(a)R^(b)),            —C(═O)R^(a), —C₁₋₄ alkyl-C(═O)R^(a), —CO₂R^(a), —C₁₋₄            alkyl-CO₂R^(a), —OCO₂R^(a), —C₁₋₄ alkyl-OCO₂R^(a),            —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —C₁₋₄            alkyl-S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b),            —C₁₋₄ alkyl-N(R^(a))SO₂R^(b), —N(R^(a))C(═O)R^(b), —C₁₋₄            alkyl-N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —C₁₋₄            alkyl-N(R^(a))CO₂R^(b), phenyl, —C₁₋₄ alkyl-phenyl, or oxo;    -   (5) —O—C₁₋₆ alkyl, optionally substituted with 1 or 2        substituents each of which is independently —OH, —O—C₁₋₄ alkyl,        —OCF₃, —S(O)_(n)R^(a), or —NH—CO₂R^(a), or —C(═O)N(R^(a)R^(b)),    -   (6) —OCF₃,    -   (7) —OH,    -   (8) fluoro, chloro, or bromo,    -   (9) —NO₂,    -   (10) —CN,    -   (1 1) —C(═O)R^(a),    -   (12) —CO₂R^(a),    -   (13) —S(O)_(n)R^(a),    -   (14) —SO₂N(R^(a)R^(b)),    -   (15) —N(R^(a)R^(b)),    -   (16) —C(═O)N(R^(a)R^(b)),    -   (17) —N(R^(a))SO₂R^(b), or    -   (18) —N(R^(a))C(═O)R^(b);    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A sixth embodiment of the present invention is a compound of Formula(I), wherein R^(2a) and R^(2b) are each independently:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₂ alkyl substituted with one substituent which is —OH,        OCH₃, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),        —CO₂R^(a), —SR^(a), —SO₂R^(a), —SO₂N(R^(a)R^(b)),        —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b),    -   (4) —CF₃,    -   (5) —CH₂-cyclopropyl,    -   (6) —CH₂-phenyl, wherein the phenyl is optionally substituted        with from 1 to 3 substituents each of which is independently        fluoro, chloro, bromo, —C₁₋₄ alkyl, —CH₂OCH₃, —CF₃, —O—C₁₋₄        alkyl, —OCF₃, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)),        —C(═O)R^(a), —CO₂R^(a), or —S(O)_(n)R^(a);    -   (7) —CH₂-heteroaryl, wherein the heteroaryl is pyridyl,        pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl,        imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,        isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, or        thiadiazolyl; and wherein the heteroaryl is optionally        substituted with 1 or 2 substituents each of which is        independently fluoro, chloro, bromo, —C₁₋₄ alkyl, —O—C₁₋₄ alkyl,        or oxo,    -   (8) —O—C₁₋₄ alkyl,    -   (9) —OCF₃,    -   (10) —OH    -   (11) fluoro, chloro, or bromo,    -   (12) —NO₂,    -   (13) —CN,    -   (14) —C(═O)R^(a),    -   (15) —CO₂R^(a),    -   (16) —S(O)_(n)R^(a),    -   (17) —SO₂N(R^(a)R^(b)),    -   (18) —N(R^(a)R^(b)),    -   (19) —C(═O)N(R^(a)R^(b)),    -   (20) —N(R^(a))SO₂R^(b), or    -   (21) —N(R^(a))C(═O)R^(b);    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of each of the fifth and sixth embodiments, each R^(a) andR^(b) is independently —H or —C₁₋₄ alkyl. In another aspect of each ofthe fifth and sixth embodiments, one of R^(2a) and R^(2b) is —H, and theother of R^(2a) and R^(2b) is as just defined in the embodiment.

A seventh embodiment of the present invention is a compound of Formula(I), wherein R^(2a) and R^(2b) are each independently:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —CF₃,    -   (4) fluoro, chloro, or bromo,    -   (5) —SO₂—C₁₋₄ alkyl,    -   (6) —S—C₁₋₄ alkyl,    -   (7) —SO₂N(—C₁₋₄ alkyl)₂,    -   (8) —C(═O)N(—C₁₋₄ alkyl)₂,    -   (9) —NHSO₂—C₁₋₄ alkyl,    -   (10) —N(—C₁₋₄ alkyl)SO₂—C₁₋₄ alkyl,    -   (11) —NHC(═O)—C₁₋₄ alkyl,    -   (12) —N(—C₁₋₄ alkyl)C(═O)—C₁₋₄ alkyl, or    -   (13) —C(═O)NH(—C₁₋₄ alkyl);    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

An eighth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R^(2a) andR^(2b) are each independently one of groups (1) to (12) as defined inthe seventh embodiment; and all other variables are as originallydefined.

In an aspect of each of the seventh and eighth embodiments, one ofR^(2a) and R^(2b) is —H, and the other of R^(2a) and R^(2b) is as justdefined in the embodiment. In an aspect of the seventh embodiment, oneof R^(2a) and R^(2b) is —H, and the other of R^(2a) and R^(2b) is:

-   -   (1) —H,    -   (2) —SO₂CH₃,    -   (3) —SO₂CH₂CH₃,    -   (4) —S—CH₃, or    -   (5) —S—CH₂CH₃.

In an aspect of the eighth embodiment, one of R^(2a) and R^(2b) is —H,and the other of R^(2a) and R^(2b) is:

-   -   (1) —H,    -   (2) —SO₂CH₃,    -   (3) —SO₂CH₂CH₃,    -   (4) —S—CH₃,    -   (5) —S—CH₂CH₃, or    -   (6) —C(═O)NH(CH₃).

A ninth embodiment of the present invention is a compound of Formula(1), wherein R³ is:

-   -   (1) —H,    -   (2) —C₁₋₆ alkyl, optionally substituted with from 1 to 5        substituents each of which is independently halogen, —OH,        —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),        —N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₄        alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C(═O)—C₁₋₄        alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),        —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a), —S(O)_(n)R^(a),        —SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂N(R^(a)R^(b)),        —N(R^(a))—SO₂—C₁₋₄ alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),        —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or -G-C₁₋₄        alkyl-C(═O)N(R^(a)R^(b)) wherein G is O or S or N(SO₂R^(a)),        -   with the proviso that none of the following substituents is            attached to the carbon in the —C₁₋₆ alkyl group that is            attached to the ring nitrogen: —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆            haloalkyl, —NO₂, —N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),            —N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆            alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C(═O)—C₁₋₆            alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),            —OCO₂R^(a), —N(R^(a))—SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂C₁₋₆            alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),            —N(R^(a))SO₂R^(b), or -G-C₁₋₆ alkyl-C(═O)N(R^(a)R^(b))            wherein G is O or N(SO₂R^(a)),    -   (3) —C₁₋₆ alkyl substituted with one of:        -   (i) —R^(k),        -   (ii) —S(O)_(n)—R^(k),        -   (iii) —S(O)_(n)—C₁₋₄ alkyl-R^(k),        -   (iv) —C(═O)—R^(k),        -   (v) —C(═O)—C₁₋₄ alkyl-R^(k),        -   (vi) —C(═O)N(R^(a))—R^(k), or        -   (vii) —C(═O)N(R^(a))—C₁₋₄ alkyl-R^(k),    -   (4) —C₂₋₆ alkyl substituted with one of:        -   (i) —O—R^(k),        -   (ii) —O—C₁₋₄ alkyl-R^(k),        -   (iii) —N(R^(a))—R^(k),        -   (iv) —N(R^(a))—C₁₋₄ alkyl-R^(k),        -   (v) —N(R^(a))C(═O)—R^(k),        -   (vi) —N(R^(a))C(═O)—C₁₋₄ alkyl-R^(k),        -   with the proviso that the substituent is not attached to the            carbon in the —C₂₋₆ alkyl group that is attached to the ring            nitrogen,    -   (5) —S(O)_(n)R^(a),    -   (6) —SO₂N(R^(a)R^(b)),    -   (7) —C₂₋₄ alkenyl, optionally substituted with one substituent        which is —C(═O)—N(R^(a)R^(b)) or —R^(k),    -   (8) —C₂₋₄ alkynyl, optionally substituted with one substituent        which is —CH₂N(R^(a)R^(b)), —CH₂OR^(a), or —R^(k),    -   (9) —R^(k),    -   (10) —S(O)_(n)—C₁₋₄ alkyl-R^(k),    -   (11) —N(R^(a))C(═O)—R^(k); or    -   (12) —N(R^(a))C(═O)—C₁₋₄ alkyl-R^(k);    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A tenth embodiment of the present invention is a compound of Formula(I), wherein R³ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl, optionally substituted with one substituent        which is —O—C₁₋₄ alkyl, —CN, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),        —N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))C(═O)CH₂N(R^(a)R^(b)),        —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a),        —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))CO₂R^(b),        —N(R^(a))—SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂CH₂N(R^(a)R^(b)), or        —N(R^(a))SO₂R^(b),        -   with the proviso that none of the following substituents is            attached to the carbon in the —C₁₋₄ alkyl group that is            attached to the ring nitrogen: —O—C₁₋₄ alkyl,            —N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),            —N(R^(a))C(═O)N(R^(a)R^(b)),            —N(R^(a))'C(═O)—CH₂N(R^(a)R^(b)),            —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —N(R^(a))CO₂R^(b),            —N(R^(a))—SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂—CH₂N(R^(a)R^(b)),            or —N(R^(a))SO₂R^(b),    -   (3) —C₁₋₄ alkyl-R^(k),    -   (4) —C₁₋₄ alkyl-C(═O)—R^(k), or    -   (5) —CH₂₋₄ alkyl-N(R^(a))—C(═O)—R_(k), with the proviso that the        substituent is not attached to the carbon in the —C₂₋₄ alkyl        group that is attached to the ring nitrogen;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

An eleventh embodiment of the present invention is a compound of Formula(1), wherein R³ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —(CH₂)₂₋₃—O—C₁₋₄ alkyl,    -   (4) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)₂,    -   (5) —(CH₂)₁₋₃—C(═O)N(—C₁₋₄ alkyl)₂,    -   (6) —(CH₂)₂₋₃—OC(═O)N(—C₁₋₄ alkyl)₂,    -   (7) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)C(═O)N(—C₁₋₄ alkyl)₂,    -   (8) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)C(═O)—CH₂N(—C₁₋₄ alkyl)₂,    -   (9) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)C(═O)—C(═O)N(—C₁₋₄ alkyl)₂,    -   (10) —(CH₂)₁₋₃—CO₂₋₄ alkyl,    -   (11) —(CH₂)₁₋₃—S(O)_(n)—C₁₋₄ alkyl,    -   (12) —(CH₂)₁₋₃—SO₂N(—C₁₋₄ alkyl)₂,    -   (13) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-CO₂—C₁₋₄ alkyl,    -   (14) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-SO₂N(—C₁₋₄ alkyl)₂,    -   (15) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-SO₂CH₂N(—C₁₋₄ alkyl)₂,    -   (16) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-SO₂—C₁₋₄ alkyl,    -   (17) —(CH₂)_(1-3—R) ^(k),    -   (18) —(CH₂)₁₋₃—C(═O)—R_(k), or    -   (19) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-C(═O)—R^(k);    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A twelfth embodiment of the present invention is a compound of Formula(I), wherein R^(k) is:

-   -   (i) —C₃₋₈ cycloalkyl,    -   (ii) aryl selected from phenyl and naphthyl, wherein the aryl is        optionally substituted with from 1 to 3 substituents each of        which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,        —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),        —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),        —N(R^(a))SO₂R^(b), —(CH₂)₁₋₂—O—C₁₋₄ alkyl, —(CH₂)₁₋₂—O—C₁₋₄        haloalkyl, —(CH₂)₁₋₂—CN, —(CH₂)₁₋₂—N(R^(a)R^(b)),        —(CH₂)₁₋₂—C(═O)N(R^(a)R^(b)), —(CH₂)₁₋₂—C(═O)R^(a),        —(CH₂)₁₋₂—CO₂R^(a), —(CH₂)₁₋₂—S(O)_(n)R^(a),        —(CH₂)₁₋₂—SO₂N(R^(a)R^(b)), —(CH₂)₁₋₂—N(R^(a))C(═O)R^(b),        —(CH₂)₁₋₂—N(R^(a))CO₂R^(b), —(CH₂)₁₋₂—N(R^(a))SO₂R^(b), phenyl,        —(CH₂)₁₋₂-phenyl, HetB, or —(CH₂)₁₋₂HetB;    -   (iii) a 4- to 7-membered saturated heterocyclic ring containing        from 1 to 4 heteratoms selected from N, O and S, wherein the        saturated heterocyclic ring is optionally substituted with from        1 to 3 substituents each of which is independently halogen,        —C₁₋₄ alkyl, oxo, phenyl, —(CH₂)₁-2-phenyl, HetC, or        —(CH₂)₁₋₂HetC, or    -   (iv) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with from 1 to        3 substituents each of which is independently halogen, —C₁₋₄        alkyl, —O—C₁₋₄ alkyl, phenyl, —(CH₂)₁₋₂-phenyl, HetC, or        —(CH₂)₁₋₂-HetC;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the twelfth embodiment, R³ is as defined in the ninthembodiment. In another aspect of the twelfth embodiment, R³ is asdefined in the tenth embodiment. In still another aspect of the twelfthembodiment, R³ is as defined in the eleventh embodiment.

A thirteenth embodiment of the present invention is a compound ofFormula (I), wherein R^(k) is:

-   -   (i) phenyl, which is optionally substituted with from 1 to 3        substituents each of which is independently halogen, —C₁₋₄        alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl or —O—C₁₋₄ haloalkyl,    -   (ii) a 5- or 6-membered saturated heterocyclic ring containing        from 1 to 4 heteratoms selected from N, O and S, wherein the        saturated heterocyclic ring is optionally substituted with from        1 to 3 substituents each of which is independently —C₁₋₄ alkyl        or oxo, or    -   (iii) a 5- or 6-membered heteroaromatic ring containing from 1        to 4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with from 1 to        3 substituents each of which is independently halogen, —C₁₋₄        alkyl, or —O—C₁₋₄ alkyl;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the thirteenth embodiment, R³ is as defined in the ninthembodiment. In another aspect of the thirteenth embodiment, R³ is asdefined in the tenth embodiment. In still another aspect of thethirteenth embodiment, R³ is as defined in the eleventh embodiment.

A fourteenth embodiment of the present invention is a compound ofFormula (I), wherein R^(k) is:

-   -   (i) phenyl which is optionally substituted with from 1 to 3        substituents each of which is independently fluoro, chloro,        bromo, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃;    -   (ii) a saturated heterocyclic ring selected from the group        consisting of piperidinyl, piperazinyl, pyrrolidinyl,        pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,        morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl,        tetrahydrothienyl, tetrahydrofuryl, thiazinanyl, thiadiazinanyl,        and dioxanyl; wherein the saturated heterocyclic ring is        optionally substituted with from 1 to 3 substituents each of        which is independently —C₁₋₄ alkyl or oxo; or    -   (iii) a heteroaromatic ring selected from the group consisting        of pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl,        thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,        oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and        thiadiazolyl; wherein the heteroaromatic ring is optionally        substituted with from 1 to 3 substituents each of which is        independently halogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the fourteenth embodiment, R³ is as defined in the ninthembodiment. In another aspect of the fourteenth embodiment, R³ is asdefined in the tenth embodiment. In still another aspect of thefourteenth embodiment, R³ is as defined in the eleventh embodiment.

A fifteenth embodiment of the present invention is a compound of Formula(I), wherein each of R⁴ and R⁵ is independently:

-   -   (1) —H,    -   (2) —C₁₋₆ alkyl, optionally substituted with from 1 to 5        substituents each of which is independently halogen, —OH,        —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),        —N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₄        alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C(═O)—C₁₋₄        alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),        —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a), —S(O)_(n)R^(a),        —SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂N(R^(a)R^(b)),        —N(R^(a))—SO₂—C₁₋₄ alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),        —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or -G-C₁₋₄        alkyl-C(═O)N(R^(a)R^(b)) wherein G is O or S or N(SO₂R^(a)),    -   (3) —SO₂N(R^(a)R^(b)), or    -   (4) —C₁₋₆ alkyl-R^(m);    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A sixteenth embodiment of the present invention is a compound of Formula(I), wherein each of R⁴ and R⁵ is independently:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl, optionally substituted with one substituent        which is —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),        —CO₂R^(a), —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), or        —N(R^(a))SO₂R^(b), or    -   (3) —C₁₋₄ alkyl-R^(m);    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A seventeenth embodiment of the present invention is a compound ofFormula (1), wherein each of R⁴ and R⁵ is independently:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —(CH₂)₁₋₃—N(—C₁₋₄ alkyl)₂,    -   (4) —(CH₂)₁₋₃—C(═O)N(—C₁₋₄ alkyl)₂,    -   (5) —(CH₂)₁₋₃—CO₂—C₁₋₄ alkyl,    -   (6) —(CH₂)₁₋₃—S(O)_(n)—C₁₋₄ alkyl,    -   (7) —(CH₂)₁₋₃—SO₂N(—C₁₋₄ alkyl)₂,    -   (8) —(CH₂)₁₋₃—N(—C₁₋₄ alkyl)-SO₂—C₁₋₄ alkyl, or    -   (9) —(CH₂)₁₋₃-R^(m);    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

An eighteenth embodiment of the present invention is a compound ofFormula (I), wherein R⁴ and R⁵ are both —H;

-   -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A nineteenth embodiment of the present invention is a compound ofFormula (I), wherein each R^(m) is independently:

-   -   (i) —C₃₋₈ cycloalkyl,    -   (ii) aryl selected from phenyl and naphthyl, wherein the aryl is        optionally substituted with from 1 to 3 substituents each of        which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,        —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),        —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),        —N(R^(a))SO₂R^(b), —(CH₂)₁₋₂—O—C₁₋₄ alkyl, —(CH₂)₁₋₂—O—C₁₋₄        haloalkyl, —(CH₂)₁₋₂—CN, —(CH₂)₁₋₂—N(R^(a)R^(b)),        —(CH₂)₁₋₂—C(═O)N(R^(a)R^(b)), —(CH₂)₁₋₂—C(═O)R^(a),        —(CH₂)₁₋₂—CO₂R^(a), —(CH₂)₁₋₂—S(O)_(n)R^(a),        —(CH₂)₁₋₂—SO₂N(R^(a)R^(b)), —(CH₂)₁₋₂—N(R^(a))C(═O)R^(b),        —(CH₂)₁₋₂—N(R^(a))CO₂R^(b), —(CH₂)₁₋₂—N(R^(a))SO₂R^(b), phenyl,        —(CH₂)₁₋₂-phenyl, HetB, or —(CH₂)₁₋₂HetB;    -   (iii) a 4- to 7-membered saturated heterocyclic ring containing        from 1 to 4 heteratoms selected from N, O and S, wherein the        saturated heterocyclic ring is optionally substituted with from        1 to 3 substituents each of which is independently halogen,        —C₁₋₄ alkyl, oxo, phenyl, —(CH₂)₁₋₂-phenyl, HetC, or        —(CH₂)₁₋₂HetC, or    -   (iv) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with from 1 to        3 substituents each of which is independently halogen, —C₁₋₄        alkyl, —O—C₁₋₄ alkyl, phenyl, —(CH₂)₁₋₂-phenyl, HetC, or        —(CH₂)₁₋₂-HetC;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the nineteenth embodiment, R⁴ and R⁵ are each as definedin the fifteenth embodiment. In another aspect of the nineteenthembodiment, R⁴ and R⁵ are each as defined in the sixteenth embodiment.In still another aspect of the nineteenth embodiment, R⁴ and R⁵ are eachas defined in the seventeenth embodiment.

A twentieth embodiment of the present invention is a compound of Formula(I), wherein each R^(m) is independently:

-   -   (i) phenyl, which is optionally substituted with from 1 to 3        substituents each of which is independently halogen, —C₁₋₄        alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl,    -   (ii) a 5- or 6-membered saturated heterocyclic ring containing        from 1 to 4 heteratoms selected from N, O and S, wherein the        saturated heterocyclic ring is optionally substituted with from        1 to 3 substituents each of which is independently —C₁₋₄ alkyl        or oxo, or    -   (iii) a 5- or 6-membered heteroaromatic ring containing from 1        to 4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with from 1 to        3 substituents each of which is independently halogen, —C₁₋₄        alkyl, or —O—C₁₋₄ alkyl;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the twentieth embodiment, R⁴ and R⁵ are each as definedin the fifteenth embodiment. In another aspect of the twentiethembodiment, R⁴ and R⁵ are each as defined in the sixteenth embodiment.In still another aspect of the twentieth embodiment, R⁴ and R⁵ are eachas defined in the seventeenth embodiment.

A twenty-first embodiment of the present invention is a compound ofFormula (I), wherein R^(m) is:

-   -   (i) phenyl which is optionally substituted with from 1 to 3        substituents each of which is independently fluoro, chloro,        bromo, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃;    -   (ii) a saturated heterocyclic ring selected from the group        consisting of piperidinyl, piperazinyl, pyrrolidinyl,        pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,        morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl,        tetrahydrothienyl, tetrahydrofuryl, thiazinanyl, thiadiazinanyl,        and dioxanyl; wherein the saturated heterocyclic ring is        optionally substituted with from 1 to 3 substituents each of        which is independently —C₁₋₄ alkyl or oxo; or    -   (iii) a heteroaromatic ring selected from the group consisting        of pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl,        thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,        oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and        thiadiazolyl; wherein the heteroaromatic ring is optionally        substituted with from 1 to 3 substituents each of which is        independently halogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the twenty-first embodiment, R⁴ and R⁵ are each asdefined in the fifteenth embodiment. In another aspect of thetwenty-first embodiment, R⁴ and R⁵ are each as defined in the sixteenthembodiment. In still another aspect of the twenty-first embodiment, R⁴and R⁵ are each as defined in the seventeenth embodiment.

A twenty-second embodiment of the present invention is a compound ofFormula (I), wherein each R^(a) and R^(b) is independently —H or —C₁₋₆alkyl;

-   -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the twenty-second embodiment, each R^(a) and R^(b) isindependently —H, methyl, or ethyl. In another aspect of thetwenty-second embodiment, each R^(a) and R^(b) is independently —H ormethyl. In still another aspect of the twenty-second embodiment, eachR^(a) and R^(b) is methyl.

A twenty-third embodiment of the present invention is a compound ofFormula (I), wherein each R^(a) and R^(b) is independently —H, —C₁₋₄alkyl, or —C₃₋₆ cycloalkyl;

-   -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

In an aspect of the twenty-third embodiment, each R^(a) and R^(b) isindependently —H, methyl, ethyl, or cyclopropyl. In another aspect ofthe twenty-third embodiment, each R^(a) and R^(b) is independently —H,methyl, or cyclopropyl.

A twenty-fourth embodiment of the present invention is a compound ofFormula (I), wherein L is

-   -   (i) a single bond,    -   (ii) —(CH₂)₁₋₄—, which is optionally substituted with        —C(═O)N(R^(a)R^(b)),    -   (iii) —(CH₂)₀₋₃—C═C—(CH₂)₁₋₃—,    -   (iv) —(CH₂)₀₋₃—C≡C—(CH₂)₁₋₃—, or    -   (v) —(CH₂)₀₋₄—(C₃₋₆ cycloalkyl)-(CH₂)₀₋₄—;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A twenty-fifth embodiment of the present invention is a compound ofFormula (I), wherein L is

-   -   (i) a single bond,    -   (ii) —(CH₂)₁₋₂—, which is optionally substituted with        —C(═O)N(R^(a)R^(b)),    -   (iii) —(CH₂)₀₋₂—C═C—CH₂—,    -   (iv) —(CH₂)₀₋₃—C≡C—CH₂—, or    -   (v) —(CH₂)₀₋₂—(C₃₋₆ cycloalkyl)-(CH₂)₀₋₂—;    -   and all other variables are as originally defined;    -   or a pharmaceutically acceptable salt thereof.

A twenty-sixth embodiment of the present invention is a compound ofFormula (I), wherein L is CH₂; and all other variables are as originallydefined;

-   -   or a pharmaceutically acceptable salt thereof.

A first class of compounds of the present invention includes anycompound of Formula (II):

wherein:

-   -   R^(1b) is —H, fluoro, chloro, bromo, —C₁₋₄ alkyl, or —CF₃;    -   R^(2a) is:        -   (1) —H,        -   (2) —C₁₋₄ alkyl,        -   (3) —CF₃,        -   (4) fluoro, chloro, or bromo,        -   (5) —SO₂—C₁₋₄ alkyl,        -   (6) —S—C₁₋₄ alkyl,        -   (7) —SO₂N(R^(a)R^(b)),        -   (8) —N(R^(a))SO₂—C₁₋₄ alkyl, or        -   (9) —C(═O)N(R^(a)R^(b));    -   R³ is:        -   (1) —H,        -   (2) —C₁₋₄ alkyl, optionally substituted with one substituent            which is —O—C₁₋₄ alkyl, —CN, —N(R^(a)R^(b)),            —C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),            —N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))C(═O)CH₂N(R^(a)R^(b)),            —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a),            —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))CO₂R^(b),            —N(R^(a))—SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂CH₂N(R^(a)R^(b)),            or —N(R^(a))SO₂R^(b),            -   with the proviso that none of the following substituents                is attached to the carbon in the —C₁₋₄ alkyl group that                is attached to the ring nitrogen: —O—C₁₋₄ alkyl,                —N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),                N(R^(a))C(═O)N(R^(a)R^(b)),                —N(R^(a))—C(═O)—CH₂N(R^(a)R^(b)),                —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —N(R^(a))CO₂R^(b),                —N(R^(a))—SO₂N(R^(a)R^(b)),                —N(R^(a))—SO₂—CH₂N(R^(a)R^(b)), or —N(R^(a))SO₂R^(b),    -   (3) —C₁₋₄ alkyl-R^(k),    -   (4) —C₁₋₄ alkyl-C(═O)—R^(k), or    -   (5) —C₂₋₄ alkyl-N(R^(a))—C(═O)—R^(k), with the proviso that the        substituent is not attached to the carbon in the —C₂₋₄ alkyl        group that is attached to the ring nitrogen;        -   wherein R^(k) is:        -   (i) phenyl, which is optionally substituted with from 1 to 3            substituents each of which is independently halogen, —C₁₋₄            alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl,        -   (ii) a 5- or 6-membered saturated heterocyclic ring            containing from 1 to 4 heteratoms selected from N, O and S,            wherein the saturated heterocyclic ring is optionally            substituted with from 1 to 3 substituents each of which is            independently —C₁₋₄ alkyl or oxo, or        -   (iii) a 5- or 6-membered heteroaromatic ring containing from            1 to 4 heteroatoms independently selected from N, O and S,            wherein the heteroaromatic ring is optionally substituted            with from 1 to 3 substituents each of which is independently            halogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl;    -   each R^(a) and R^(b) is independently —H or —C₁₋₄ alkyl; and    -   n is an integer equal to zero, 1 or 2;    -   or a pharmaceutically acceptable salt thereof.

A second class of compounds of the present invention includes anycompound of Formula (II), wherein:

-   -   R^(1b) is fluoro, chloro, bromo, methyl, or ethyl;    -   R^(2a) is:        -   (1) —H,        -   (2) methyl or ethyl,        -   (3) fluoro,        -   (4) —SO₂—C₁₋₄ alkyl,        -   (5) —S—C₁₋₄ alkyl,        -   (6) —SO₂N(—C₁₋₄ alkyl)₂,        -   (7) —NHSO₂—C₁₋₄ alkyl,        -   (8) —N(—C₁₋₄ alkyl)SO₂—C₁₋₄ alkyl, or        -   (9) —C(═O)NH(—C₁₋₄ alkyl);    -   R³ is:        -   (1) —H,        -   (2) —C₁₋₄ alkyl,        -   (3) —(CH₂)₂₋₃—O—C₁₋₄ alkyl,        -   (4) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)₂,        -   (5) —(CH₂)₁₋₃—C(═O)N(—C₁₋₄ alkyl)₂,        -   (6) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)C(═O)N(—C₁₋₄ alkyl)₂,        -   (7) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)C(═O)—C(═O)N(—C₁₋₄ alkyl)₂,        -   (8) —(CH₂)₁₋₃—CO₂—C₁₋₄ alkyl,        -   (9) —(CH₂)₁₋₃—S(O)_(n)—C₁₋₄ alkyl,        -   (10) —(CH₂)₁₋₃—SO₂N(—C₁₋₄ alkyl)₂,        -   (11) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-SO₂N(—C₁₋₄ alkyl)₂,        -   (12) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-SO₂—C₁₋₄ alkyl,        -   (13) —(CH₂)₁₋₃—R^(k),        -   (14) —(CH₂)₁₋₃—C(═O)—R^(k), or        -   (15) —(CH₂)₂₋₃—N(R^(a))—C(═O)—R^(k);            -   wherein R^(k) is:            -   (i) phenyl, which is optionally substituted with from 1                to 3 substituents each of which is independently                halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or                —O—C₁₋₄ haloalkyl,            -   (ii) a 5- or 6-membered saturated heterocyclic ring                containing from 1 to 4 heteratoms selected from N, O and                S, wherein the saturated heterocyclic ring is optionally                substituted with from 1 to 3 substituents each of which                is independently —C₁₋₄ alkyl or oxo, or            -   (iii) a 5- or 6-membered heteroaromatic ring containing                from 1 to 4 heteroatoms independently selected from N, O                and S, wherein the heteroaromatic ring is optionally                substituted with from 1 to 3 substituents each of which                is independently halogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl;                and    -   n is an integer equal to zero, 1 or 2;    -   or a pharmaceutically acceptable salt thereof.

A third class of compounds of the present invention includes anycompound of Formula (II) as defined in the second class, or apharmaceutically acceptable salt thereof, except that R^(2a) is not—C(═O)NH(—C₁₋₄ alkyl).

A fourth class of compounds of the present invention includes compoundsof Formula (II), wherein:

-   -   R^(1b) is fluoro;    -   R^(2a) is:        -   (1) —H,        -   (2) fluoro,        -   (3) —SO₂—C₁₋₄ alkyl,        -   (4) —S—C₁₋₄ alkyl,        -   (5) —SO₂N(—C₁₋₄ alkyl)₂,        -   (6) —NHSO₂—C₁₋₄ alkyl,        -   (7) —N(—C₁₋₄ alkyl)SO₂—C₁₋₄ alkyl, or        -   (8) —C(═O)NH(—C₁₋₄ alkyl);    -   R³ is:        -   (1) —H,        -   (2) —C₁₋₄ alkyl,        -   (3) —(CH₂)₂₋₃—O—C₁₋₄ alkyl,        -   (4) —(CH₂)₂₋₃—N(—C₁₋₂ alkyl)₂,        -   (5) —(CH₂)₁₋₃—C(═O)N(—C₁₋₂ alkyl)₂,        -   (6) —(CH₂)₂₋₃—N(—C₁₋₂ alkyl)C(═O)N(—C₁₋₂ alkyl)₂,        -   (7) —(CH₂)₂₋₃—N(—C₁₋₂ alkyl)C(═O)—C(═O)N(—C₁₋₂ alkyl)₂,        -   (8) —(CH₂)₁₋₃—S(O)_(n)—C₁₋₂ alkyl,        -   (9) —(CH₂)₁₋₃—SO₂N(—C₁₋₂ alkyl)₂,        -   (10) —(CH₂)₂₋₃—N(—C₁₋₂ alkyl)-SO₂N(—C₁₋₂ alkyl)₂,        -   (11) —(CH₂)₂₋₃—N(—C₁₋₂ alkyl)-SO₂—C₁₋₂ alkyl,        -   (12) —(CH₂)₁₋₃—R^(k), or        -   (13) —(CH₂)₁₋₃—C(═O)—R^(k);            -   wherein R^(k) is:            -   (i) phenyl, which is optionally substituted with from 1                to 3 substituents each of which is independently                halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or                —O—C₁₋₄ haloalkyl,            -   (ii) a 5- or 6-membered saturated heterocyclic ring                containing from 1 to 4 heteratoms selected from N, O and                S, wherein the saturated heterocyclic ring is optionally                substituted with from 1 to 3 substituents each of which                is independently —C₁₋₄ alkyl or oxo, or            -   (iii) a 5- or 6-membered heteroaromatic ring containing                from 1 to 4 heteroatoms independently selected from N, O                and S, wherein the heteroaromatic ring is optionally                substituted with from 1 to 3 substituents each of which                is independently halogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl;                and    -   n is an integer equal to zero, 1 or 2;    -   or a pharmaceutically acceptable salt thereof.

A fifth class of compounds of the present invention includes anycompound of Formula (II) as defined in the fourth class, or apharmaceutically acceptable salt thereof, except that R^(2a) is not—C(═O)NH(—C₁₋₄ alkyl).

In a feature of each of the preceding classes, R^(k) is:

-   -   (i) phenyl which is optionally substituted with from 1 to 3        substituents each of which is independently fluoro, chloro,        bromo, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃;    -   (ii) a saturated heterocyclic ring selected from the group        consisting of piperidinyl, piperazinyl, pyrrolidinyl,        pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,        morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl,        tetrahydrothienyl, tetrahydrofuryl, thiazinanyl, thiadiazinanyl,        and dioxanyl; wherein the saturated heterocyclic ring is        optionally substituted with from 1 to 3 substituents each of        which is independently —C₁₋₄ alkyl or oxo; or    -   (iii) a heteroaromatic ring selected from the group consisting        of pyridyl, pyrrolyl, pyrazinyl,-pyrimidinyl, pyridazinyl,        thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,        oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and        thiadiazolyl; wherein the heteroaromatic ring is optionally        substituted with from 1 to 3 substituents each of which is        independently halogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl.

It is to be understood that additional embodiments of the presentinvention include, but are not limited to, compounds of Formula Iwherein each of two or three or more of L, R^(1a), R^(1b), R^(1c),R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R^(a), R^(b), R^(k) and R^(m) isindependently defined in accordance with its definition in one of theembodiments or an aspect thereof as set forth above, or in accordancewith its definition in one of the foregoing classes set forth above or asub-class or feature thereof. Any and all possible combinations of thesevariables in Formula I are additional embodiments within the scope ofthe present invention.

An aspect of the present invention is a compound selected from the groupconsisting of

-   -   N-(4-fluorobenzyl)-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-{2-[(dimethylamino)sulfonyl]ethyl}-N-(4-fluorobenzyl)4hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-{2-[(dimethylamino)sulfonyl]ethyl}-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-(1,4-dioxan-2-ylmethyl)-N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-(1,4-dioxan-2-ylmethyl)-N-[4-fluoro-2-(methylthio)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-(1,4-dioxan-2-ylmethyl)-N-[4-fluoro-2-(methylsulfonyl)benzyl]4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthylidine-3-carboxamide;    -   N-(4-fluorobenzyl)-4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-1-{2-[methyl(methylsulfonyl)-amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-[(1,1-Dioxidotetrahydrothien-3-yl)methyl]-N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl]4-hydroxy-1-[2-(methylsulfonyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-ethyl-N-[4-fluoro-2-(methylthio)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-ethyl-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-(4-fluorobenzyl)-4-hydroxy-1-[2-(methylsulfinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamiide;    -   N-(4-fluorobenzyl)-4-hydroxy-1-[2-(methylsulfonyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-(4-fluorobenzyl)-4-hydroxy-1-(2-morpholin-4-ylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(1H-1,2,4-triazol-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-[2-(dimethylamino)-2-oxoethyl]-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-(2-methoxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-benzyl-n-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-{2-[[(dimethylamino)sulfonyl](methyl)amino]ethyl}-N-[4-fluoro-2-(methylsulfonyl)benzyl]4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthylidine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-(2-morpholin-4-yl-2-oxoethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl)-1-{2-[[(dimethylamino)carbonyl](methyl)-amino]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   1-benzyl-N-{4-fluoro-2-[(methylamino)carbonyl]benzyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide;    -   and pharmaceutically acceptable salts thereof.

Other embodiments of the present invention include the following:

-   -   (a) A pharmaceutical composition comprising a therapeutically        effective amount of a compound of Formula (I) and a        pharmaceutically acceptable carrier.    -   (b) A pharmaceutical composition which comprises the product        prepared by combining (e.g., mixing) a therapeutically effective        amount of a compound of Formula (I) and a pharmaceutically        acceptable carrier.    -   (c) The pharmaceutical composition of (a) or (b), further        comprising a therapeutically effective amount of an HIV        infection/AIDS treatment agent selected from the group        consisting of HIV/AIDS antiviral agents, immunomodulators, and        anti-infective agents.    -   (d) The pharmaceutical composition of (c), wherein the HIV        infection/AIDS treatment agent is an antiviral selected from the        group consisting of HIV protease inhibitors, non-nucleoside HIV        reverse transcriptase inhibitors, and nucleoside HIV reverse        transcriptase inhibitors.    -   (e) A combination useful for inhibiting HIV integrase, for        treating or preventing infection by HIV, or for preventing,        treating or delaying the onset of AIDS, which is a        therapeutically effective amount of a compound of Formula (I)        and a therapeutically effective amount of an HIV infection/AIDS        treatment agent selected from the group consisting of HIV/AIDS        antiviral agents, immunomodulators, and anti-infective agents.    -   (f) The combination of (e), wherein the HIV infection/AIDS        treatment agent is an antiviral selected from the group        consisting of HIV protease inhibitors, non-nucleoside HIV        reverse transcriptase inhibitors and nucleoside HIV reverse        transcriptase inhibitors.    -   (g) A method of inhibiting HIV integrase in a subject in need        thereof which comprises administering to the subject a        therapeutically effective amount of a compound of Formula (I).    -   (h) A method of preventing or treating infection by HIV in a        subject in need thereof which comprises administering to the        subject a therapeutically effective amount of a compound of        Formula (I).    -   (i) The method of (h), wherein the compound of Formula (I) is        administered in combination with a therapeutically effective        amount of at least one antiviral selected from the group        consisting of HIV protease inhibitors, non-nucleoside HIV        reverse transcriptase inhibitors, and nucleoside HIV reverse        transcriptase inhibitors.    -   (j) A method of preventing, treating or delaying the onset of        AIDS in a subject in need thereof which comprises administering        to the subject a therapeutically effective amount of a compound        of Formula (I).    -   (k) The method of (j), wherein the compound is administered in        combination with a therapeutically effective amount of at least        one antiviral selected from the group consisting of HIV protease        inhibitors, non-nucleoside HIV reverse transcriptase inhibitors,        and nucleoside HIV reverse transcriptase inhibitors    -   (l) A method of inhibiting HIV integrase in a subject in need        thereof which comprises administering to the subject the        pharmaceutical composition of (a), (b), (c) or (d) or the        combination of (e) or (f).    -   (m) A method of preventing or treating infection by HIV in a        subject in need thereof which comprises administering to the        subject the pharmaceutical composition of (a), (b), (c) or (d)        or the combination of (e) or (f).    -   (n) A method of preventing, treating or delaying the onset of        AIDS in a subject in need thereof which comprises administering        to the subject the pharmaceutical composition of (a), (b), (c)        or (d) or the combination of (e) or (f).

The present invention also includes a compound of the present invention(i) for use in, (ii) for use as a medicament for, or (iii) for use inthe preparation of a medicament for: (a) inhibiting HIV protease, (b)preventing or treating infection by HIV, or (c) preventing, treating ordelaying the onset of AIDS. In these uses, the compounds of the presentinvention can optionally be employed in combination with one or moreHIV/AIDS treatment agents selected from HIV/AIDS antiviral agents,anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(n) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, aspects, classes, sub-classes, or features of the compoundsdescribed above. In all of these embodiments, the compound mayoptionally be used in the form of a pharmaceutically acceptable salt.

As used herein, the term “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) means linear orbranched chain alkyl groups having from 1 to 6 carbon atoms and includesall of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-,sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C₁₋₄ alkyl” meansn-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term “—C₁₋₆ alkyl-” refers to a C₁ to C₆ linear or branched alkylgroup as just defined which is bivalent. It can alternatively bereferred to as “C₁₋₆ alkylene” or “C₁₋₆ alkanediyl”. A class ofalkylenes of particular interest with respect to the invention is—(CH₂)₁₋₆—, and sub-classes of particular interest include —(CH₂)₁₋₄—,—(CH₂)₁₋₃—, —(CH₂)₁₋₂—, and —CH₂—.

The term “C₀” as employed in expressions such as “C₀₋₆ alkyl” means adirect covalent bond. For example, when L in Compound I is —(C₀₋₃alkyl)-C═C—(C₁₋₃ alkyl)-, then L is —C═C—(C₁₋₃ alkyl)-, when the firstalkyl group is “C₀”. As a further, more specific example, when L is—(C₀₋₃ alkyl)-C═C—(C₁₋₃ alkyl)-, wherein the first alkyl group is “C₀”and the second alkyl group is “C₁”, then the compound is a compound ofFormula (III):

The term “C₂₋₆ alkenyl” (or “C_(2-C) ₆ alkenyl”) means linear orbranched chain alkenyl groups having from 2 to 6 carbon atoms andincludes all of the hexenyl and pentenyl isomers as well as 1-butenyl,2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl(or vinyl). Similar terms such as “C₂₋₄ alkenyl” have an analogousmeaning.

The term “C₂₋₅ alkynyl” (or “C₂-C₅ alkynyl”) means linear or branchedchain alkynyl groups having from 2 to 5 carbon atoms and includes all ofthe pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl,1-propynyl, 2-propynyl, and ethynyl (or acetylenyl). Similar terms suchas “C₂₋₄ alkynyl” have an analogous meaning.

The term “C₃₋₈ cycloalkyl” (or “C_(3-C) ₈ cycloalkyl”) means a cyclicring of an alkane having three to eight total carbon atoms (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl). Similar terms such as “C₃₋₆ cycloalkyl” have an analogousmeaning.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term “C₁₋₆ haloalkyl” (which may alternatively be referred to as“C₁-C₆ haloalkyl” or “halogenated C₁-C₆ alkyl”) means a C₁ to C₆ linearor branched alkyl group as defined above with one or more halogensubstituents. The term “C₁₋₄ haloalkyl” has an analogous meaning. Theterm “C₁₋₆ fluoroalkyl” has an analogous meaning except that the halogensubstituents are restricted to fluoro. Suitable fluoroalkyls include theseries (CH₂)₀₋₄CF₃ (i.e., trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.).

The term “carbocycle” (and variations thereof such as “carbocyclic” or“carbocyclyl”) as used herein refers to (i) a C₃ to C₈ monocyclic,saturated or unsaturated ring, (ii) a C₇ to C₁₂ bicyclic ring system, or(iii) a C₁₁ to C₁₆ tricyclic ring system, wherein each ring in (ii) or(iii) is independent of or fused to the other ring or rings and eachring is saturated or unsaturated. The carbocycle may be attached to therest of the molecule at any carbon atom which results in a stablecompound. When the carbocyclic ring has substituents, it is understoodthat the substituents may be attached to any atom in the ring whichresults in a stable chemical structure.

The fused bicyclic carbocycles are a subset of the carbocycles; i.e.,the term “fused bicyclic carbocycle” generally refers to a C₇ to C₁₂bicyclic ring system in which each ring is saturated or unsaturated andtwo adjacent carbon atoms are shared by each of the rings in the ringsystem. Fused tricyclic carbocycles have an analogous meaning. A subsetof the fused bicyclic carbocycles are those bicyclic carbocycles inwhich one ring is a benzene ring and the other ring is saturated orunsaturated, with attachment via any carbon atom that results in astable compound. Representative examples of this subset include thefollowing:

Aryl groups form a subset of the carbocycles; i.e., the term “aryl” asused herein refers to an aromatic carbocyclic ring or an aromaticcarbocyclic fused ring system. The fused ring system contains two ormore carbocyclic rings in which each ring shares two adjacent carbonatoms with at least one other ring. The aryl group may be attached tothe rest of the molecule at any carbon atom which results in a stablecompound.

A subset of aryl groups particularly suitable for use in the presentinvention (e.g., in the definition of R^(2a) or R^(2b), when R^(2a) orR^(2b) is —C₁₋₆ alkyl substituted with aryl) includes those selectedfrom phenyl, naphthyl, anthryl, and phenanthryl. Another particularlysuitable subset of aryl groups is phenyl and naphthyl. Still anotherparticularly suitable subset of aryl groups is phenyl per se.

A subset of carbocycles particularly suitable for use in the presentinvention (e.g., in the definition of R^(k) or R^(m)) includes anycarbocycle which is (i) —C₃₋₈ cycloalkyl or (ii) aryl. Anotherparticularly suitable subset includes any carbocycle which is —C₃₋₈cycloalkyl, phenyl, naphthyl, anthryl, or phenanthryl. Still anotherparticularly suitable subset includes any carbocycle which is —C₃₋₈cycloalkyl, phenyl, or naphthyl. Yet another particularly suitablesubset is phenyl and naphthyl, and still another is phenyl per se.

The term “heterocycle” (and variations thereof such as “heterocyclic” or“heterocyclyl”) refers to (i) a 4- to 8-membered, saturated orunsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ringsystem, or (iii) an 11 to 16-membered tricyclic ring system; whereineach ring in (ii) or (iii) is independent of or fused to the other ringor rings and each ring is saturated or unsaturated, and the monocyclicring, bicyclic ring system, or tricyclic ring system contains one ormore heteroatoms (e.g., from 1 to 6 heteroatoms, from 1 to 5heteroatoms, or from 1 to 4 heteroatoms) independently selected from N,O and S and a balance of carbon atoms (the monocylic ring typicallycontains at least one carbon atom and the ring systems typically containat least two carbon atoms); and wherein any one or more of the nitrogenand sulfur heteroatoms is optionally oxidized, and any one or more ofthe nitrogen heteroatoms is optionally quaternized. The heterocyclicring may be attached to the rest of the molecule via any heteroatom orcarbon atom in the ring, provided that attachment results in thecreation of a stable structure. When the heterocyclic ring hassubstituents, it is understood that the substituents may be attached toany atom in the ring, whether a heteroatom or a carbon atom, providedthat a stable chemical structure results.

Saturated heterocyclics form a subset of the heterocycles; i.e., theterm “saturated heterocyclic” generally refers to a heterocycle asdefined above in which the entire ring system (whether mono- orpoly-cyclic) is saturated. The term “saturated heterocyclic ring” refersto a 4- to 7-membered saturated monocyclic ring which consists of carbonatoms and one or more heteroatoms independently selected from N, O andS. Representative examples include piperidinyl, piperazinyl, azepanyl

pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,isothiazolidinyl, tetrahydrothienyl, tetrahydrofuryl (ortetrahydrofuranlyl), thiazinanyl

thiadiazinanyl

and dioxanyl.

Heteroaromatics form another subset of the heterocycles; i.e., the term“heteroaromatic” (alternatively “heteroaryl”) generally refers to aheterocycle as defined above in which the entire ring system (whethermono- or poly-cyclic) is an aromatic ring system. The term“heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ringwhich consists of carbon atoms and one or more (e.g., from 1 to 4)heteroatoms independently selected from N, O and S. Representativeexamples of heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.

Representative examples of bicyclic heterocycles include benzotriazolyl,indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl,quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl

and benzo-1,3-dioxolyl

Representative examples of tricyclic heterocycles includephenothiazinyl, carbazolyl, beta-carbolinyl, tetrahydro-beta-carbolinyl,acridinyl, phenazinyl, and phenoxazinyl.

A subset of heterocycles particularly suitable for use in the presentinvention (e.g., in the definition of R^(k) or R^(m)) includes anyheterocycle which is (i) a 4- to 7-membered saturated heterocyclic ringcontaining from 1 to 4 heteratoms selected from N, O and S, or (ii) a 5-or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S. Another particularly suitablesubset includes any heterocycle which is (i) a 5 or 6-membered saturatedheterocyclic ring containing from 1 to 4 heteratoms independentlyselected from N, O and S, or (ii) a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS. Still another particularly suitable subset includes any heterocyclewhich is (i) a 5 or 6-membered saturated heterocyclic ring containingfrom 1 to 3 heteratoms independently selected from N, O and S, or (ii) a5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S. Still another particularlysuitable subset includes any heterocycle which is (i) a 5 or 6-memberedsaturated heterocyclic ring containing from 1 or 2 heteratomsindependently selected from N, O and S, or (ii) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 N atoms.

A subset of heteroaryl groups particularly suitable for use in thepresent invention (e.g., in the definition of R^(2a) or R^(2b), whenR^(2a) or R^(2b) is —C₁₋₆ alkyl substituted with heteroaryl) includesany heteroaryl which is a 5- or 6-membered heteraromatic ring containingfrom 1 to 4 heteroatoms or a 9- or 10-membered bicyclic heteroaromaticring system containing from 1 to 6 heteroatoms, wherein the heteroatomsin the heteroaryl are independently selected from N, O and S. Anotherparticularly suitable subset of aryl groups includes any heteroarylwhich is a 5- or 6-membered heteraromatic ring containing from 1 to 4heteroatoms. Still another particularly suitable subset of heteroarylgroups includes any heteroaryl which is pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, thienyl, furanyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, or thiadiazolyl.

Unless expressly stated to the contrary, an “unsaturated” ring is apartially or fully unsaturated ring. For example, an “unsaturatedmonocyclic C₆ carbocycle” refers to cyclohexene, cyclohexadiene, andbenzene.

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocycle described as containing from “1 to4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4heteroatoms.

When any variable (e.g., R^(a), R^(b), or R^(m)) occurs more than onetime in any constituent or in Formula I or in any other formuladepicting and describing compounds of the invention, its definition oneach occurrence is independent of its definition at every otheroccurrence. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “substituted” (e.g., as in “aryl which is optionallysubstituted with one or more substituents . . . ”) includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution (including multiple substitution at the same site)is chemically allowed.

The compounds of the present invention may have asymmetric centers andmay occur, except when specifically noted, as mixtures of stereoisomersor as individual diastereomers, or enantiomers, with all isomeric formsbeing included in the present invention.

Compounds of Formula I wherein R³═H may also occur as tautomers thereof.Tautomers include, but are not limited to:

It is understood that the present invention includes all tautomers ofthe hydroxynaphthyridinone compounds embraced by Formula I, both singlyand in mixtures.

The compounds of the present invention are useful in the inhibition ofHIV integrase, the prevention or treatment of infection by humanimmunodeficiency virus (HIV) and the prevention, treatment or the delayin the onset of consequent pathological conditions such as AIDS.Preventing AIDS, treating AIDS, delaying the onset of AIDS, orpreventing or treating infection by HIV is defined as including, but notlimited to, treatment of a wide range of states of HIV infection: AIDS,ARC (AIDS related complex), both symptomatic and asymptomatic, andactual or potential exposure to HIV. For example, the compounds of thisinvention are useful in treating infection by HIV after suspected pastexposure to HIV by such means as blood transfusion, exchange of bodyfluids, bites, accidental needle stick, or exposure to patient bloodduring surgery.

The compounds of this invention are useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVintegrase, e.g., by competitive inhibition. Thus the compounds of thisinvention are commercial products to be sold for these purposes.

The compounds of the present invention can be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to a salt which possesses the effectiveness ofthe parent compound and which is not biologically or otherwiseundesirable (e.g., is neither toxic nor otherwise deleterious to therecipient thereof). Suitable salts include acid addition salts whichmay, for example, be formed by mixing a solution of the compound of thepresent invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, or benzoic acid. When the compounds of the invention carry anacidic moiety, suitable pharmaceutically acceptable salts thereof caninclude alkali metal salts (e.g., sodium or potassium salts), alkalineearth metal salts (e.g., calcium or magnesium salts), and salts formedwith suitable organic ligands such as quaternary ammonium salts. Also,in the case of an acid (—COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed to modify thesolubility or hydrolysis characteristics of the compound.

For the purpose of preventing or treating HIV infection or preventing,treating or delaying the onset of AIDS, the compounds of the presentinvention can be administered orally, parenterally (includingsubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques), by inhalation spray, or rectally, inthe form of a unit dosage of a pharmaceutical composition containing atherapeutically effective amount of the compound and conventionalnon-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention mean providing thecompound to the individual in need of treatment. When a compound of theinvention is provided in combination with one or more other activeagents (e.g., antiviral agents useful for treating HIV infection orAIDS), “administration” and its variants are each understood to includeconcurrent and sequential provision of the compound and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombining the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and notdeleterious to the recipient thereof.

The term “subject” (which may be alternatively referred to herein as“patient”) as used herein refers to an animal, preferably a mammal, mostpreferably a human, who has been the object of treatment, observation orexperiment.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease being treated. When the active compound (i.e., activeingredient) is administered as the salt, references to the amount ofactive ingredient are to the free acid or free base form of thecompound.

The pharmaceutical compositions can be in the form oforally-administrable suspensions or tablets or capsules, nasal sprays,sterile injectible preparations, for example, as sterile injectibleaqueous or oleagenous suspensions or suppositories. These compositionscan be prepared by methods and contain excipients which are well knownin the art. Suitable methods and ingredients are described inRemington's Pharmaceutical Sciences, 18^(th) edition, edited by A. R.Gennaro, Mack Publishing Co., 1990, which is herein incorporated byreference in its entirety.

The compounds of this invention can be administered orally in a dosagerange of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per dayin a single dose or in divided doses. One preferred dosage range is 0.01to 500 mg/kg body weight per day orally in a single dose or in divideddoses. Another preferred dosage range is 0.1 to 100 mg/kg body weightper day orally in single or divided doses. For oral administration, thecompositions can be provided in the form of tablets or capsulescontaining 1.0 to 500 milligrams of the active ingredient, particularly1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

As noted above, the present invention is also directed to use of the HIVintegrase inhibitor compounds of the present invention with one or moreagents useful in the treatment of HIV infection or AIDS. For example,the compounds of this invention may be effectively administered, whetherat periods of pre-exposure and/or post-exposure, in combination witheffective amounts of one or more of the HIV/AIDS antivirals,imunomodulators, antiinfectives, or vaccines useful for treating HIVinfection or AIDS. Suitable agents include those listed in the followingTable:

Antivirals

Manufacturer (Tradename and/or Drug Name Location) Indication (Activity)abacavir Glaxo Welcome HIV infection, AIDS, ARC GW 1592 (ZIAGEN ®)(nucleoside reverse 1592U89 transcriptase inhibitor) abacavir +lamivudine + zidovudine GlaxoSmithKline HIV infection, AIDS, ARC(TRIZIVIR ®) (nucleoside reverse transcriptase inhibitors) acemannanCarrington Labs ARC (Irving, TX) ACH 126443 Achillion Pharm. HIVinfections, AIDS, ARC (nucleoside reverse transcriptase inhibitor)acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combinationwith AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 TanoxBiosystems HIV infection, AIDS, ARC adefovir dipivoxil Gilead HIVinfection, AIDS, ARC GS 840 (reverse transcriptase inhibitor) AL-721Ethigen ARC, PGL, HIV positive, (Los Angeles, CA) AIDS alpha interferonGlaxo Wellcome Kaposi's sarcoma, HIV, in combination w/Retrovir AMD3100AnorMed HIV infection, AIDS, ARC (CXCR4 antagonist) amprenavir GlaxoWellcome HIV infection, AIDS, 141 W94 (AGENERASE ®) ARC (PI) GW 141VX478 (Vertex) ansamycin Adria Laboratories ARC LM 427 (Dublin, OH)Erbamont (Stamford, CT) antibody which neutralizes Advanced BiotherapyAIDS, ARC pH labile alpha aberrant Concepts (Rockville, interferon MD)AR177 Aronex Pharm HIV infection, AIDS, ARC atazanavir (BMS 232632)Bristol-Myers-Squibb HIV infection, AIDS, ARC (ZRIVADA ®) (proteaseinhibitor) beta-fluoro-ddA Nat'l Cancer Institute AIDS-associateddiseases BMS-232623 Bristol-Myers Squibb/ HIV infection, AIDS,(CGP-73547) Novartis ARC (protease inhibitor) BMS-234475 Bristol-MyersSquibb/ HIV infection, AIDS, (CGP-61755) Novartis ARC (proteaseinhibitor) capravirine Pfizer HIV infection, AIDS, (AG-1549, S-1153) ARC(non-nucleoside reverse transcriptase inhibitor) CI-1012 Warner-LambertHIV-1 infection cidofovir Gilead Science CMV retinitis, herpes,papillomavirus curdlan sulfate AJI Pharma USA HIV infectioncytomegalovirus immune MedImmune CMV retinitis globin cytovene Syntexsight threatening CMV ganciclovir peripheral CMV retinitis delavirdinePharmacia-Upjohn HIV infection, AIDS, (RESCRIPTOR ®) ARC (non-nucleosidereverse transcriptase inhibitor) dextran Sulfate Ueno Fine Chem. Ind.AIDS, ARC, HIV Ltd. (Osaka, Japan) positive asymptomatic ddC Hoffman-LaRoche HIV infection, AIDS, ARC (zalcitabine, (HIVID ®) (nuclesodiereverse dideoxycytidine) transcriptase inhibitor) ddI Bristol-MyersSquibb HIV infection, AIDS, ARC; dideoxyinosine (VIDEX ®) combinationwith AZT/d4T (nucleoside reverse transcriptase inhibitor) DPC 681 & DPC684 DuPont HIV infection, AIDS, ARC (protease inhibitors) DPC 961 & DPC083 DuPont HIV infection AIDS, ARC (non-nucleoside reverse transcriptaseinhibitors) EL10 Elan Corp, PLC HIV infection (Gainesville, GA)efavirenz DuPont HIV infection, AIDS, (DMP 266) (SUSTIVA ®) ARC(non-nucleoside RT Merck (STOCRIN ®) inhibitor) famciclovir Smith Klineherpes zoster, herpes simplex emtricitabine Triangle Pharmaceuticals HIVinfection, AIDS, ARC FTC (COVIRACIL ®) (nucleoside reverse EmoryUniversity transcriptase inhibitor) emvirine Triangle PharmaceuticalsHIV infection, AIDS, ARC (COACTINON ®) (non-nucleoside reversetranscriptase inhibitor) enfuvirtide Trimeris & Roche HIV infection,AIDS, ARC T-20 (FUSEON ®) (fusion inhibitor) HB Y097 Hoechst MarionRoussel HIV infection, AIDS, ARC (non-nucleoside reverse transcriptaseinhibitor) hypericin VIMRx Pharm. HIV infection, AIDS, ARC recombinanthuman Triton Biosciences AIDS, Kaposi's sarcoma, interferon beta(Almeda, CA) ARC interferon alfa-n3 Interferon Sciences ARC, AIDSindinavir Merck (CRIXIVAN ®) HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis JE2147/AG1776 Agouron HIV infection, AIDS,ARC (protease inhibitor) KNI-272 Nat'l Cancer Institute HIV-assoc.diseases lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, (EPIVIR ®)ARC (nucleoside reverse transcriptase inhibitor); also with AZTlobucavir Bristol-Myers Squibb CMV infection lopinavir (ABT-378) AbbottHIV infection, AIDS, ARC (protease inhibitor) lopinavir + ritonavirAbbott (KALETRA ®) HIV infection, AIDS, ARC (ABT-378/r) (proteaseinhibitor) mozenavir AVID (Camden, NJ) HIV infection, AIDS, ARC(DMP-450) (protease inhibitor) nelfinavir Agouron HIV infection, AIDS,(VIRACEPT ®) ARC (protease inhibitor) nevirapine Boeheringer HIVinfection, AIDS, Ingleheim ARC (non-nucleoside (VIRAMUNE ®) reversetranscriptase inhibitor) novapren Novaferon Labs, Inc. HIV inhibitor(Akron, OH) peptide T Peninsula Labs AIDS octapeptide (Belmont, CA)sequence PRO 140 Progenics HIV infection, AIDS, ARC (CCR5 co-receptorinhibitor) PRO 542 Progenics HIV infection, AIDS, ARC (attachmentinhibitor) trisodium Astra Pharm. Products, CMV retinitis, HIVinfection, phosphonoformate Inc other CMV infections PNU-140690Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) probucolVyrex HIV infection, AIDS RBC-CD4 Sheffield Med. Tech HIV infection,AIDS, (Houston TX) ARC ritonavir Abbott HIV infection, AIDS, (ABT-538)(RITONAVIR ®) ARC (protease inhibitor) saquinavir Hoffmann-LaRoche HIVinfection, AIDS, (FORTOVASE ®) ARC (protease inhibitor) stavudine; d4TBristol-Myers Squibb HIV infection, AIDS, ARC didehydrodeoxy- (ZERIT ®)(nucleoside reverse thymidine transcriptase inhibitor) T-1249 TrimerisHIV infection, AIDS, ARC (fusion inhibitor) TAK-779 Takeda HIVinfection, AIDS, ARC (injectable CCR5 receptor antagonist) tenofovirGilead (VIREAD ®) HIV infection, AIDS, ARC (nucleotide reversetranscriptase inhibitor) tipranavir (PNU-140690) Boehringer IngelheimHIV infection, AIDS, ARC (protease inhibitor) TMC-120 & TMC-125 TibotecHIV infections, AIDS, ARC (non-nucleoside reverse transcriptaseinhibitors) TMC-126 Tibotec HIV infection, AIDS, ARC (proteaseinhibitor) valaciclovir Glaxo Wellcome genital HSV & CMV infectionsvirazole Viratek/ICN (Costa asymptomatic HIV positive, ribavirin Mesa,CA) LAS, ARC zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC,(RETROVIR ®) Kaposi's sarcoma in combination with other therapies(nucleoside reverse transcriptase inhibitor)

Immuno-Modulators

Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS BropiriminePharmacia Upjohn advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC(Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi's sarcoma LederleLabs EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 FukiImmunoPharm blocks HIV fusion with CD4+ cells Gamma Interferon GenentechARC, in combination w/TNF (tumor necrosis factor) Granulocyte MacrophageGenetics Institute AIDS Colony Stimulating Factor Sandoz GranulocyteMacrophage Hoeschst-Roussel AIDS Colony Stimulating Factor ImmunexGranulocyte Macrophage Schering-Plough AIDS, combination w/AZT ColonyStimulating Factor HIV Core Particle Rorer seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-La Roche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in CD4 cell Interleukin-2 (aldeslukin)counts Immune Globulin Cutter Biological pediatric AIDS, in ntravenous(human) (Berkeley, CA) combination w/AZT IMREG-1 Imreg (New Orleans,AIDS, Kaposi's sarcoma, LA) ARC, PGL IMREG-2 Imreg (New Orleans, AIDS,Kaposi's sarcoma, LA) ARC, PGL Imuthiol Diethyl Dithio Merieux InstituteAIDS, ARC Carbamate Alpha-2 Interferon Schering Plough Kaposi's sarcomaw/AZT, AIDS Methionine-Enkephalin TNI Pharmaceutical AIDS, ARC (Chicago,IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-TripeptideGranulocyte Colony Amgen AIDS, in combination Stimulating Factor w/AZTRemune Immune Response Corp. immunotherapeutic rCD4 RecombinantGenentech AIDS, ARC Soluble Human CD4 rCD4-IgG hybrids AIDS, ARCRecombinant Soluble Biogen AIDS, ARC Human CD4 Interferon Alfa 2aHoffman-La Roche Kaposi's sarcoma, AIDS, ARC, in combination w/AZTSK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute Tumor Necrosis Factor;Genentech ARC, in combination TNF w/gamma Interferon etanercept ImmunexCorp rheumatoid arthritis (ENBREL ®) infliximab Centocor rheumatoidarthritis and (REMICADE ®) Crohn's disease

Anti-Infectives

Drug Name Manufacturer Indication Clindamycin with Pharmacia Upjohn PCPPrimaquine Fluconazole Pfizer cryptococcal meningitis, candidiasisPastille Nystatin Pastille Squibb Corp. prevention of oral candidiasisOrnidyl Eflornithine Merrell Dow PCP Pentamidine Isethionate LyphoMedPCP treatment (IM & IV) (Rosemont, IL) Trimethoprim antibacterialTrimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine isethionate Fisons Corporation PCP prophylaxis forinhalation Spiramycin Rhone-Poulenc cryptosporidia diarrheaIntraconazole-R51211 Janssen Pharm. histoplasmosis; cryptococcalmeningitis Trimetrexate Warner-Lambert PCP

Other

Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi'ssarcoma Recombinant Human Ortho Pharm. Corp. severe anemia assoc.Erythropoietin with AZT therapy Recombinant Human Serono AIDS-relatedwasting, Growth Hormone cachexia Leukotriene B4 Receptor — HIV infectionAntagonist Megestrol Acetate Bristol-Myers Squibb treatment of anorexiaassoc. w/AIDS Soluble CD4 Protein and — HIV infection DerivativesTestosterone Alza, Smith Kline AIDS-related wasting Total EnteralNutrition Norwich Eaton diarrhea and Pharmaceuticals malabsorption,related to AIDS

It will be understood that the scope of combinations of the compounds ofthis invention with HIV/AIDS antivirals, immunomodulators,anti-infectives or vaccines is not limited to the list in the aboveTable, but includes in principle any combination with any pharmaceuticalcomposition useful for the treatment of AIDS. The HIV/AIDS antiviralsand other agents will typically be employed in these combinations intheir conventional dosage ranges and regimens as reported in the art,including the dosages described in the Physicians' Desk Reference,54^(th) edition, Medical Economics Company, 2000, which is incorporatedherein by reference in its entirety. The dosage ranges for a compound ofthe invention in these combinations are the same as those set forthabove.

Abbreviations used in the instant specification, particularly theSchemes and Examples, include the following:

-   -   AIDS=acquired immunodeficiency syndrome    -   APCI=atmospheric pressure chemical ionization mass spectroscopy    -   ARC=AIDS related complex    -   BOC or Boc=t-butyloxycarbonyl    -   BOP=benzotriazol-1-yloxytris-(dimethylamino)phosphonium        hexafluorophosphate    -   CBZ=carbobenzoxy (alternatively, benzyloxycarbonyl)    -   DIEA or DIPEA=diisopropylethylamine (or Hunig's base)    -   DIPEA=diisopropylethylamine=Hunig's base    -   DMF=dimethylformamide    -   DMSO=dimethyl sulfoxide    -   EDC or EDAC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide    -   EIMS=eletron ionization mass spectroscopy    -   ESMS=eletron spray mass spectroscopy    -   EtOAc=ethyl acetate    -   EtOH=ethanol    -   HRMS=high resolution mass spectroscopy    -   m-CPBA=meta-chloroperbenzoic acid    -   MeOH=methanol    -   HIV=human inmmunodeficiency virus    -   HOAT=1-hydroxy-7-azabenzotriazole    -   HPLC=high performance liquid chromatography    -   Me=methyl    -   MS=mass spectroscopy    -   NBS=N-bromosuccinimide    -   NMR=nuclear magnetic resonance    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography    -   UV=ultraviolet

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to the person of ordinary skill in the art in lightof the following reaction schemes and examples. Unless otherwiseindicated, all variables are as defined above.

The compounds of the present invention can be prepared by the couplingof suitable 1,5-naphthyridine-3-carboxylic acids (or acid derivativessuch as acid halides or esters) with the appropriate amines, asrepresented by the following general scheme:

Methods for coupling carboxylic acids (and acid derivatives) with aminesto form carboxamides are well known in the art. Suitable methods aredescribed, for example, in Jerry March, Advanced Organic Chemistry, 3rdedition, John Wiley & Sons, 1985, pp. 370-376. Amines of formula 1-1 canbe prepared using, for example, the methods described in Richard Larock,Comprehensive Organic Transformations, VCH Publishers Inc, 1989, pp385-438, or routine variations thereof. Schemes 2 to 4 below illustrateand expand upon the chemistry portrayed in Scheme 1.

Compounds of Formula 1-2 in which R³=H can be prepared in accordancewith Scheme 2, wherein 3-amino-2-carboxy pyridine 2-1 (which can beprepared in accordance with Sucharda, Chem. Ber. 1925, 1727) can beesterified in acid and an alcohol to give the aminoester 2-2 in the formof a salt. Such methods are well known in the art and are described, forexample, in J. March, Advanced Organic Chemistry, 3^(rd) edition, JohnWiley & Sons, 1985, pp. 348-351, in Madrigal et al., Tetrahedron:Asymmetry 2000, 11: 3515-352, 2000, and in Culbertson et al., J. Am.Chem. Soc. 2000, 122: 4032-4038. The ester can be obtained as the freebase through neutralization by chromatography or by an aqueous workup,after which aminoester 2-2 can be reacted with an appropriate base andmethyl-3-chloro-3-oxo propionate to give the acylated amine 2-3. Asimilar type of acylation is described in J. Org. Chem. 1996, 61:1872-1874. Alternatively, aminoester 2-2 can be treated with adialkylmalonate at elevated temperature to accomplish the acylation(see, e.g., Chem. Pharm. Bull. 1993, 41: 1163-1165). When excess base ispresent, the acylated intermediate can undergo Dieckmann cyclization togive the 1,5-napthyridin-2-one-3-carboxylate ester 2-4 (see J.Heterocyclic Chem. 1998, 35: 627-636 and J. Heterocyclic Chem. 1993, 30:909-912). The ester 2-4 can then be heated in an alcohol in the presenceof an appropriate amine to give the 3-amide. (See The Chemistry ofAmides, edited by S. Patai, Wiley Interscience, 1970, p. 96).

Compounds of Formula 1-2 in which R³ is other than H can be prepared inaccordance with Scheme 3, wherein 3-fluoro-2-cyanopyridine 3-1 (whichcan be prepared in accordance with Sakamoto et al., Chem. Pharm. Bull.1985, 33: 565-571) can be combined with an appropriately derivatizedamine 3-2 in a suitable solvent (e.g., DMSO) and heated in the presenceof base (e.g., a trialkylamine such as DIPEA). The resulting 2-cyanoderivative 3-3 can then be treated with an alcohol, HCl and water underPinner conditions to give aminoester 3-4 as a salt. A discussion of thePinner reaction can be found in The Chemistry of the Cyano Group, editedby S. Patai, Wiley-Interscience, 1970, p. 264. Because protonation ofthe aminocyanopyridine can decrease the reactivity of the cyano group, alarge excess of HCl and prolonged reaction time under pressure istypically required in order to make the intermediate imidate. Refluxingthe imidate with water will afford the aminoester. After an aqueousworkup to obtain the aminoester in free base form, the aminoester can betreated with an appropriate base (e.g., an alkali metal alkoxide such asNaOMe) and methyl-3-chloro-3-oxo propionate to give, after cyclization,the 1,5-napthyridin-2-one-3-carboxylate ester 3-6 (see, e.g., J.Heterocyclic Chem. 1998, 35: 627-636 and J. Heterocyclic Chem. 1993, 30:909-912), which can then be heated in an alcohol in the presence of anappropriate amine to give the 3-amide.

Scheme 4 illustrates a variation in the coupling reaction set forth inScheme 1 for the case in which one of R^(2a) and R^(2b) in amine 1-1 isalkylsulfonyl. In the scheme, amine reactant 4-1 containing ano-alkylthio substituent on its phenyl ring is coupled to the1,5-napthyridin-2-one-3-carboxylate ester 4-2 to provide amide 4-3,which is oxidized to the final product 4-4 using m-CPBA or anotheroxidant known in the art, such as those described in J. March, AdvancedOrganic Chemistry, 3^(rd) edition, John Wiley & Sons, 1985, p. 1089. Thealkylthio-containing amine reactant 4-1 can be prepared by methods knownin the art, including via the formation of aryl anions using themetal-halogen exchange reaction of aryl halogens with strong lithiumbases. This chemistry is described, for example, in B. Wakefield,Chemistry of Organolithium Compounds, Pergamon Press, Oxford, 1974. Asan example of the application of this approach,4-fluoro-2-methylthio-benzylamine can be prepared by the metal halogenexchange of 2-bromo4-fluorobenzoic acid by first deprotonating the acidwith Grignard reagent, then conducting the metal-bromine exchange with astrong base like n-butyllithium, and then trapping withdimethyldisulfide (see, e.g., Synthetic Methods 1993, 56(1): 2128) toobtain 2-methylthio-4-fluorobenzoic acid. The benzoic acid can then beconverted to the primary amide using standard coupling conditions (seeM. Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, NewYork, 1984) and the amide reduced to the benzyl amine using a strongreducing agent, such as those described in J. March, Advanced OrganicChemistry, 3^(rd) edition, John Wiley & Sons, 1985, p. 815). Theresulting 4-fluoro-2-methylthiobenzylamine can then be coupled andoxidized into the desired naphthyridine product in the manner set forthin Scheme 4.

The methyl sulfone can alternatively be incorporated into the benzylamine before the coupling step. The appropriate4-fluoro-2-methylsulfonyl benzylamine can be prepared in a 3-stepprocess, in which 2,4-difluorobenzonitrile is first treated withthiomethoxide in the presence of an aprotic solvent such as toluene.Similar displacements are discussed in J. March, Advanced OrganicChemistry, 3^(rd) edition, John Wiley & Sons, 1985, p. 589. Theresulting 2-methylsulfide can then be oxidized to the sulfone asdiscussed above, followed by reduction of the cyano group with hydrogenand palladium catalysis in the presence of acid to afford thebenzylamine. Such reductions are described in J. March, Advanced OrganicChemistry, 3^(rd) edition, John Wiley & Sons, 1985, p. 815.

Scheme 5 illustrates a variation in the preparation of 5-N-substitutedcompounds. In the scheme, the acylated intermediate 3-5 is treated witha base such as sodium methoxide and the resulting bis-sodium salt 5-1 isisolated. This salt, which is very water soluble, is then treated underphase transfer conditions with a suitable alkyl halide to give thebis-alkylated product 5-2. Similar reactions are described by J. March,Advanced Organic Chemistry, 4^(th) edition, J. Wiley & Sons, 1992, p.362-365. The 7-ester is then hydrolyzed with NaOH to give the acid 5-3.Coupling conditions as described in Scheme 1 then give the 7-amide 5-4,and the 8-O-alkyl group is then removed with strong acid such astrifluoroacetic acid (TFA) to give the final product 5-5. Generalmethods for similar cleavage of phenolic alkyl groups are described inT. W. Greene, Protective Groups in Organic Synthesis, 3^(rd) edition,John Wiley & Sons, 1999, p. 246-292.

In the processes for preparing compounds and intermediates of thepresent invention set forth in the foregoing schemes, functional groupsin various moieties and substituents may be sensitive or reactive underthe reaction conditions employed and/or in the presence of the reagentsemployed. Such sensitivity/reactivity can interfere with the progress ofthe desired reaction to reduce the yield of the desired product, orpossibly even preclude its formation. Accordingly, it may be necessaryor desirable to protect sensitive or reactive groups on any of themolecules concerned. Protection can be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 and in T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known in the art. Alternatively theinterfering group can be introduced into the molecule subsequent to thereaction step of concern. For example, if one or more of thesubstituents R^(1a-c), R^(2a-b), R³, R⁴ and R⁵ in compound 1-1 caninterfere with the coupling reaction between compounds 1-1 and 1-2 ofScheme 1, the substituent can be incorporated into the molecule in apost-coupling step to afford Compound I.

The following examples serve only to illustrate the invention and itspractice. The examples are not to be construed as limitations on thescope or spirit of the invention.

EXAMPLE 1N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

Step 1: Preparation of methyl 3-aminopyridine-2-carboxylate

Methanol (75 mL) was cooled to 0° C. and treated dropwise withthionylchloride (3.5 mL, 48 mmol). 3-aminopyridine-2-carboxylic acid(0.9 g, 6.52 mmol, prepared as described by Sucharda, Chem. Ber. 1925,1727) was added and the mixture brought to reflux. Over the next twodays, two more MeOH/thionyl chloride mixtures were made and added to thereaction. The reaction was evaporated to dryness, then treated withthionyl chloride (5.7 mL, 78.3 mmole) in 75 mL of MeOH and refluxed fortwo more days. The reaction was evaporated to dryness andchromatographed on silica eluting with 9:1:1 EtOH/NH4OH(H₂O to givemethyl 3-aminopyridine-2-carboxylate as a yellow solid.

¹NMR (DMSO-d₆, 400 MHz) δ 7.84 (1H, dd, J=1.3, 4 Hz), 7.28 (1H, dd ,J=4.0, 8.4 Hz), 7.21 (1H, dd, J=1.5, 8.4 Hz ), 6.67 (1H, bs), 3.80 (3H,s) ppm.

MS calc'd for C₇H₈N₂O₂ 152(M), found 153 (MH+).

The compound was also alternatively prepared as follows:Step 1a: Preparation of 3-aminopyridine-2-carbonitrile.

A solution of 3-fluoro-2-cyanopyridine (Sakamoto et. al., Chem. Pharm.Bull. 1985, 33: 565-571) ( 10 g, 82 mmol) in DMSO (30 mL) was placed ina pressure vessel and saturated with ammonia gas. The reaction wascapped and heated to 70 degrees C. overnight. The reaction was cooled,vented and re-saturated with ammonia, then sealed and re-heated forseveral hours. The reaction was cooled, vented, diluted with CHCl₃ andthe solids that had formed were filtered off. The solution was added tothe top of a silica gel column (150 mm×7 inches) saturated with CHCl₃and the column was eluted with a gradient of 100% CHCl₃ to 100% CHCl₃saturated with NH₃. The fractions were collected and concentrated togive the product which contained some residual DMSO. This was used a inthe next step.

¹NMR (CDCl₃, 400 MHz) δ 7.83 (1H, dt, J=1.37, 4.2 Hz), 7.28 (1H, dd,J=4.3, 8.6 Hz), 7.18 (1H, dt, J=1.37, 8.6 Hz), 6.22 (2H, bs) ppm.Step 1b: Preparation of methyl 3-aminopyridine-2-carboxylate

A solution of 3-aminopyridine-2-carbonitrile (9.7g, 81.8 mmol) in MeOH(100 mL) was placed in a round bottom pressure vessel. The solution wascooled to −78° C. and HCl gas was bubbled through the solution until thevolume of the solution had noticeably increased. The flask was sealedand the reaction warmed to room temperature and stirred overnight. Atthis time, LCMS (sampled after re-cooling the reaction to −78° C.)showed only a small amount of starting cyano compound remaining. Water(14 mL, 818 mmol) was added and the reaction transferred to a flaskequipped with a reflux condenser. The reaction was refluxed overnight.The solution was concentrated and the remaining solution was basifiedwith 1N NaOH to pH 9, then extracted with CHCL3 repeatedly until verylittle UV-active material was removed. The organic layers were driedover Na₂SO₄, filtered and evaporated to give the product as a pinksolid.

¹NMR (CDCl3, 400 MHz) δ 8.06 (1H, dd, J=1.46,4.2 Hz), 7.21 (1H, dd,J=4.2, 8.5 Hz), 7.04 (1H, dd, J=1.46, 8.4 Hz), 5.8 (2H, bs), 3.97 (3H,s) ppm.

MS calc'd for C₇H₈N₂O₂ 152(M), found 153 (MH+)Step 2: Preparation of methyl3-[(3-methoxy-3-oxopropanoyl)amino]pyridine-2-carboxylate

A solution of methyl 3-aminopyridine-2-carboxylate (0.25 g, 1.6 mmol) inpyridine (3 mL) was cooled to 0° C. and treated with Hunig's base(DIPEA, 0.86 mL, 4.9 mmol) and methyl 3-chloro-3-oxopropionate (0.18 mL,1.6 mmol). The reaction was allowed to warm to room temperature. Overthe next several hours, 3 more equivalents of the acid chloride wasadded. The reaction was evaporated and re-dissolved in CHCl₃, washedwith NH₄Cl and evaporated to give an oil that was purified on silicawith a gradient of 80-95% EtOAc/Hexanes to give the product as a whiteoil. The oil was a mixture of mono- and bis-acylated products that wastaken on to the next reaction.

Alternatively, methyl 3-aminopyridine-2-carboxylate (0.565 g, 3.4 mmol)was combined with dimethylmalonate (5 g, 37.4 mmol) and heated to 125°C. in a sealed tube. The reaction was stirred for 3 days. The volatileswere removed in vacuo and the crude material was taken on to the nextstep.

Rf (silica, 20% Hexanes/EtOAc)=0.46 (blue under UV light).Step 3: Preparation of methyl4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate

Sodium methoxide (0.73 g, 13.5 mmol) was added to 2 methyl3-[(3-methoxy-3-oxopropanoyl)amino)pyridine-2-carboxylate (0.9 g, 3.4mmol) dissolved in THF (20 mL). The reaction was stirred overnight.Water was added and the solvents removed. The residue was dissolved inwater and purified by reverse phase HPLC eluting with a gradient of5-40% acetonitrile/water (0.1% TFA) to give the product as a yellowsolid.

¹H NMR (DMSO-d₆, 400MHz) δ 11.7 (1H, bs), 8.53 (1H, d, J=4.2 Hz), 7.70(1H, d, J=8.4 Hz), 7.65 (1H, dd, J=4.2, 8.2 Hz), 3.77 (3H, s) ppm.

Step 4. Preparation ofN-(4-fluorobenzyl)4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide.

A mixture of methyl4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.2 g, 0.91mmol) and 4-fluorobenzyl amine(Aldrich, 0.31 mL, 2.72 mmol) in absoluteethanol (5 mL) was heated to 100° C. for 6 hours. A thick paste formed.The reaction was diluted with water and the solids collected. The crudematerial was purified by preparative reverse phase HPLC eluting with agradient of 5-95% acetonitrile/water (0.1% TFA). The productprecipitated from the column fractions was collected to afford thedesired product as a white solid.

¹H NMR (DMSO, 400MHz) δ 12.0 (1H, bs), 10.63, (1H, bs), 8.58 (1H, d,J=4.0 Hz), 7.75 (1H, d, J=8.8 Hz), 7.67 (1H, dd, J=4.2, 8.5 Hz), 7.42(2H, dd, J=5.6, 8.4 Hz), 7.2 (2H, m), 4.58 (2H, d, J=5.7 Hz) ppm.

HRMS: calc'd for C₁₆H₁₂FN₃O₃+1H=314.0936, observed 314.0946.

C, H, N calc'd for C₁₆H₁₂FN₃O₃C=60.99, H=3.90, N=13.34, found C=60.93,H=3.80, N=13.02.

EXAMPLE 2 1-{2-[(dimethylamino)sulfonyl]ethyl}-N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

Step 1: Preparation of benzyl 2-(chlorosulfonyl)ethylcarbamate

This compound was prepared using the method of T. S. Widlanski and J.Huang, Tet. Lett. 1992, 33: 2657. A solution of triphenylphosphine (17.6g, 67.4 mmol) in dry CH₂Cl₂ (90 mL) was cooled to zero degrees C undernitrogen and treated with neat sulfuryl chloride (5.96 mL, 74.2 mmol) togive a yellow solution. The solution was recooled to 5 degrees C. andcrushed solid sodium 2-{[(benzyloxy)carbonyl]amino}ethanesulfonate (12g, 42.6 mmol) prepared as described by Bricas et al., Biochimica etBiophysica Acta 1955, (18), 358, was added all at once to give a whitesuspension. The reaction was allowed to warm to room temperature andstirred for 3 hours. The volatiles were removed in vacuo to give anoily/solid residue that was suspended in EtOAc and added to the top of asilica column (3 inches by 150 mm) packed in EtOAc. The product waseluted with EtOAc and the UV active fractions were combined andevaporated to give the product as a white solid.

¹H NMR (CDCl₃, 400 MHz) δ 7.35 (5H, bs), 5.20 (1H, bs), 5.12 (2H, bs ),3.89 (2H, bs), 3.85 (2H, bs) ppm.Step 2: Preparation of benzyl 2-[(dimethylamino)sulfonyl]ethylcarbamate

A solution of dry CHCl₃ (150 mL)in an oven dried flask was tared andgaseous dimethylamine was bubbled into the solution until the gain intare was 3.4 g. A dropping funnel was added, the flask was flushed withnitrogen and the solution cooled to 0° C. Benzyl2-(chlorosulfonyl)ethylcarbamate (8.8 g, 31.6 mmol) in CHCl₃ (20 mL) wasadded dropwise. The reaction was warmed to room temperature, transferredto a separatory funnel and the solution was washed twice with 10% KHSO₄solution. The organic layer was dried over Na₂SO₄, filtered andevaporated to give the crude product as an oil that was used as is inthe next step.

¹H NMR (CDCl₃, 400 MHz) δ 7.35 (5H, bs), 5.45 (1H, bs), 5.11 (2H, bs ),3.69 (2H, m), 3.13 (2H, m), 2.86 (6H, s) ppm.Step 3: Preparation of 2-[(dimethylamino)sulfonyl]ethanaminium chloride

Benzyl 2-[(dimethylamino)sulfonyl]ethylcarbamate (8.8 g, 30.7 mmol) wassuspended/dissolved in 6N HCl (75 mL) and the mixture was heated to 90°C. The solids dissolved. After 1.5 hours the reaction was cooled andextracted with ether. The aqueous layer was evaporated to give a stickywhite solid. The ether layer was found to contain unreacted startingmaterial. This was retreated with 6 N HCl at room temperature overnight.The reaction was washed with ether and the aqueous layer combined withthe previously isolated product and evaporated to give a white solid.

¹H NMR (DMSO-D₆, 400 MHz) δ 8.2 (2H, bs), 3.43 (2H, m), 3.15 (2H, m),2.80 (6H, s) ppm.Step 4: Preparation of2-[(2-cyanopyridin-3-yl)amino]-N,N-dimethylethanesulfonamide

3-fluoro-2-cyanopyridine (Sakamoto et. al., Chem. Pharm. Bull. 1985, 33:565-571)(1 g, 8.2 mmol) was placed in a high pressure tube equipped witha stir bar. DMSO (7 mL), Hunig's base (1.57 mL, 9.0 mmol) and2-[(dimethylamino)sulfonyl)-ethanaminium chloride (1.7 g, 9.0 mmol) wereadded and the vessel was sealed and heated to 80° C. for 5.5 hours, thenstirred at room temperature overnight. The reaction was treated with anadditional 0.3 equivalent of Hunig's base and 0.2 equivlanet of theamine salt and heated for 3 hours, but the reaction progressed nofurther. The mixture was cooled, added to the top of a silica gel column(60 mm by 7 inches) packed in EtOAc and the column eluted with EtOAc.Careful cutting of fractions allowed isolation of the product afterevaporation as a clear, colorless oil that solidified upon standing.

¹H NMR (CDCl₃, 400 MHz) δ 8.05 (1H, dd, J=1.0, 4.4 Hz), 7.34 (1H, dd,J=4.6, 8.6 Hz), 7.10 (1H, d, J=8.6 Hz), 5.20 (1H, bs), 3.75 (2H, dd,J=6.3, 12.6 Hz), 3.2 (2H, m), 2.92 (6H, s) ppm.Step 5: Preparation methyl3-({2-[(dimethylamino)sulfonyl]ethyl}amino)-pyridine-2-carboxylate

2-[(2-cyanopyridin-3-yl)amino]-N,N-dimethylethanesulfonamide (1.4 g, 5.5mmol) was dissolved in 50 mL MeOH and placed in a 100 mL pressure flask.The solution was cooled to −78° C. and HCl gas was bubbled through thesolution until the volume of the solution had noticeably increased. Theflask was sealed and the reaction warmed to room temperature and stirredfor 4 hours. At this time, LCMS (sampled after re-cooling the reactionto −78° C.) showed only a small amount of starting cyano compoundremaining. Water (1 mL, 55 mmol) was added and the reaction transferredto a flask equipped with a reflux condenser. The reaction was refluxedfor 1.5 hours, stirred at room temperature overnight, then refluxed for2 more hours, then stirred at room temperature for 48 hours. Thesolution was evaporated to dryness to give a green/yellow foam that wasthen partitioned between CHCl₃ and saturated NaHCO₃. The layers wereseparated and the aqueous was extracted circa 10 times or until verylittle UV-active material was removed. The organic layers were driedover Na₂SO₄, filtered and evaporated to give the product as a clear oilthat solidified upon standing.

¹H NMR (CDCl₃, 400 MHz) δ 8.05 (1H, d, J=4.2 Hz), 7.34 (1H, dd, J=4.2,8.6 Hz), 7.12 (1H, d, J=8.6 Hz), 3.97 (3H, s), 3.75 (2H, dd, J=6.6, 13.1Hz), 3.22 m), 2.90 (6H, s) ppmStep 6: Preparation of methyl1-{2-[(dimethylamino)sulfonyl]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate

Methyl 3-({2-[(dimethylamino)sulfonyl]ethyl}amino)pyridine-2-carboxylate(0.877 g, 3.05 mmol) was dissolved in dry THF (10 mL) and cooled to 0°C. NaH (338mg, 60% suspension in oil, 8.45 mmol) was added and aprecipitate formed. The slurry was treated with methyl3-chloro-3-oxopropionate (0.410 mL, 3.82 mmol) and 3 drops of MeOH andallowed to warm and stir overnight. The reaction was concentratedsomewhat in vacuo, then poured into water. The mixture was extractedonce with CHCL₃, then acidified and extracted repeatedly with CHCl₃until only a trace of UV active material is removed. The acidic organicextracts were dried over Na2SO4, filtered and evaporated to give theproduct as a pink foam.

¹H NMR (CDCl₃, 400 MHz), δ 8.70 (1H, d, J=3.8 Hz), 7.92 (1H, d, J=8.5Hz), 7.67 (1H, dd, J=4.2, 8.7 Hz), 4.6 (2H, m), 4.07 (3H, s), 3.34 (2H,m), 2.91 (6H, m) ppm.

Step 7: Preparation of1-{2-[(dimethylamino)sulfonyl]ethyl}-N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

Methyl 1-{2-[(dimethylamino)sulfonyl]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.3 g,0.84 mmol) was suspended in 8 mL of absolute EtOH and treated with4-fluorobenzyl amine (0.29 mL, 2.53 mmol). The mixture was brought toreflux for 2.5 hours, cooled, and the solids collected and washed with alittle cold EtOH to give the product as a white solid.

¹H NMR (CDCl₃, 400 MHz) δ 10.4 (1H, bs), 8.75 (1H, d, J=4.3 Hz), 7.92(1H, d, J=8.7 Hz), 7.66 (1H, dd, J=4.2, 8.7 Hz), 7.36 (2H, dd, J=5.4,8.6 Hz), 7.05 (2H, m), 4.6 (4H, m), 3.28 (2H, m), 2.91 (6H, s) ppm.

HRMS: calc'd for C₂₀H₂₁FN₄O₅S+1H=449.1290, observed 449.1286.

C, H, N calc'd for C₂₀H₂₁FN₄O₅S C=53.56, H=4.72, N=12.49, found C=53.51,H=4.58, N=12.42.

EXAMPLE 3 1-{2-[(dimethylamino)sulfonyl]ethyl}-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

Step 1: Preparation of 4-fluoro-2-(methylthio)benzoic acid.

A solution of 2-bromo4-fluorobenzoic acid (15 g, 68.5 mmol, MarshalltonResearch Laboratories) in THF (150 mL) under argon at 0° C. was treatedwith chloro(methyl)magnesium (5.64 g, 75.34 mmol, 2.94 M in THF) over 5minutes. The temperature during addition was maintained below 10° C. Theresulting solution was cooled to −78° C. and n-butyllithium (9.65 g,150.7 mmol, 2.5M in hexanes) was added over 10 minutes. The reaction waskept below −65° C. during the addition. The reaction was stirred at −78°C. for 50 minutes. A solution of (methyldithio)methane (38.71 g, 410.9mmol) in THF (20 mL), precooled to −78° C., was added by cannula. Thereaction was stirred for 10 minutes, warmed to zero ° C and stirred atzero ° C. for 2 hours until a solid began to precipitate. The reactionwas allowed to warm to 25° C. and stirred overnight. The reaction waspoured into 1N HCl and extracted with EtOAc. The water layer wasextracted with EtOAc twice more, the organic layers were combined, driedover Na₂SO₄, filtered and evaporated. The crude solid was suspended in5% EtOAc/Hexanes and stirred for an hour, then filtered and dried togive the product as a white solid.

¹H NMR (d-DMSO, 400MH) δ 7.98 (1H, dd, J=8.8, 6.4 Hz), 7.15 (1H, d,J=10.8 Hz), 7.05 (1H, dd, J=8.8, 6.4 Hz), 2.41 (3H, bs) ppm.

EI HRMS: exact mass calc'd for C₈H₇FO₂S 186.0151 (M), found 186.0151.Step 2. Preparation of 4-fluoro-2-(methylthio)benzamide.

To a solution of 4-fluoro-2-(methylthio)benzoic acid (8.1 g, 43.6 mmol)in degassed DMF (100 mL) under nitrogen was added ammonium chloride(4.66 g, 87.2 mmol) followed by 1-hydroxy-7-azabenzotriazole (11.87 g,87.2 mmol) and N,N,N-diisopropylethylamine (30.38 mL, 174.4 mmol). Tothis mixture was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride and the reaction was stirred for 16 hour. LCMS analysisindicated that the reaction was complete. The DMF was removed in vacuoand the residue was partitioned between methylene chloride (800 mL) and5% aqueous HCl (400 mL). The organic phase was washed with water (400mL), saturated sodium bicarbonate solution (400 mL), and brine (400 mL).The organics were dried over Na₂SO₄, filtered, and reduced to a smallvolume in vacuo. The product crystallized upon solvent reduction. Thecrystals were filtered and dried iii vacuo to afford the title compound.

¹H NMR (CDCl₃, 400MHz) δ 7.67 (1H, dd, J=8.4, 5.86 Hz), 7.00 (1H, dd,J=9.89, 2.4 Hz), 6.88 (1H, dd, J=8.4, 2.4 Hz), 2.48 (3H, s) ppm.

APCI HRMS: exact mass calc'd for C₈H₈FNOS 186.0783 (MH⁺), found186.0365.Step 3: Preparation of 1-[4-fluoro-2-(methylthio)phenyl]methanamine

A slurry of 4-fluoro-2-(methylthio)benzamide (9 g, 48.6 mmol) in diethylether (500 mL) was cooled to 0° C. under nitrogen and lithium aluminumhydride (5.53 g, 145.8 mmol, 1.0 M in diethyl ether) was added dropwise.The reaction was allowed to stir with slow warming to 25° C. overnight.The reaction was quenched via the addition of water (5.53 mL), 15% NaOH(5.53 mL) and water (16 mL). The mixture was stirred, the lithium saltsprecipitated out and were filtered off. The organic filtrate was washedwith saturated sodium bicarbonate (300 mL) and brine (300 mL), driedover Na₂SO₄, filtered and reduced to a small volume. The resulting brownoil was placed under high vacuum to give the desired compound as a freebase.

¹H NMR (d-DMSO, 400 MHz) δ 7.43 (1H, t, J=7 Hz), 7.03 (1H, dd, J=10.0,2.4 Hz), 6.94 (1H, ddd, J=8.8, 6.4, 2.4 Hz ), 3.64 (2H, s), 2.50 (3H, s)ppm.

APCI HRMS: exact mass calc'd for C₈H₁₀FNS 172.0591 (MH⁺), found172.0566.Step 4: Preparation of1-{2-[(dimethylamino)sulfonyl]ethyl}-N-[4-fluoro-2-(methylthio)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Example 2, methyl1-{2-[(dimethylamino)sulfonyl]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(0.3 g, 0.84 mmol) was suspended in 8 mL of absolute EtOH and treatedwith 1-[4-fluoro-2-(methylthio)phenyl]methanamine (0.21 g, 1.3 mmol).The mixture was brought to reflux for 4.5 hours, cooled, and the solidscollected and washed with a little cold EtOH to give the product as awhite solid.

¹H NMR (CDCl₃, 400 Mz) δ 10.53 (1H, bs), 8.67 (1H, d, J=4.1 Hz), 8.05(1H, d, J=8.8 Hz), 7.83 (1H, dd, J=4.1, 8.6 Hz), 7.35 (1H, m), 7.15 (1H,dd, J=2.2, 10 Hz), 6.99 (1H, app. dt, J=2.1, 8.4 Hz), 4.6 (4H, m), 3.28(2H, t, J=7.6Hz), 2.79 (6H, s), 2.55 (3H, s) ppm.

Step 5:1-{2-[(dimethylamino)sulfonyl]ethyl}-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

1-{2-[(dimethylamino)sulfonyl]ethyl}-N-[4-fluoro-2-(methylthio)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide(0.194g, 0.39 mmol) was dissolved in a 1:2 mixture of CHCl₃ and CH₂Cl₂(10 mL) and treated with m-CPBA (380 mg, 70% pure, 1.54 mmol). Thesolution was stirred at room temperature overnight. The reaction wastreated with 3 drops of DMSO and stirred for 30 minutes, then pouredinto a separatory funnel and extracted twice with saturated NaHCO₃solution. The organic layer was dried over Na₂SO₄, filtered andevaporated to give the product as a foam. A portion was purified onreverse phase HPLC eluting with a gradient of 95:5 to 5:95water/acetonitrile (0.1% TFA) and the product precipitated out of thefractions and was collected as a white solid.

¹H NMR (DMSO-d6, 400 Mz) δ 10.73 (1H, bs), 8.67 (1H, d, J=3.8 Hz), 8.05(1H, d, J=8.8 Hz), 7.84 (1H, dd, J=4.3, 8.7 Hz), 7.75 (1H, dd, J=2.6,8.6 Hz), 7.69(1H, dd, J=5.5, 8.6 Hz), 7.61 (1H, app. dt, J=2.8, 8.3 Hz),4.94 (2H, J=5.7 Hz), 4.60 (2H, m), 3.41 (5H, m ), 2.80 (6H, s), ppm.

HRMS: calc'd for C₂₁H₂₃FN₄O₇S₂+1H=527.1065, observed 527.1051.

C, H, N calc'd for C₂₁H₂₃FN₄O₇S₂ C=47.90, H=4.40, N=10.64, foundC=47.85, H=4.27, N=10.43.

EXAMPLE 41-(1,4-dioxan-2-ylmethyl)-N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In the manner described in Example 2, 3-fluoro-2-cyanopyridine wasreacted with R,S-1,4-dioxan-2-ylmethylamine (Chembridge Corporation),the cyano group transformed into a methyl ester via the Pinner reaction,the resulting amine acylated with methyl 3-chloro-3-oxopropionate andcyclized to the 1,5-naphthyridine-6-one, and the amide formed byreaction with 4-fluorobenzylamine to give the product as a yellow-greensolid.

¹H NMR (DMSO-d6, 400 MH) δ 10.62 (1H, bs), 8.63 (1H, d, J=4.2 Hz), 8.18(1H, d, J=8.9 Hz), 7.77 (1H, ddd, J=1.3, 4.2, 8.7 Hz), 7.44 (2H,m),7.19(2H, m), 4.58 (2H, J=5.1 Hz), 4.30 (2H, m), 3.84 (1H, m), 3.80 (1H,d, J=12.1 Hz), 3.66 (1H, m), 3.60 (1H, m), 3.45 (2H, m), 3.40 (1H, m)ppm.

C, H, N calc'd for C₂₁H₂₀FN₃O₅ C=61.01, H=4.88, N=10.16, found C=60.77,H=4.71, N=9.97.

EXAMPLE 51-(1,4-dioxan-2-ylmethyl)-N-[4-fluoro-2-(methylthio)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Examples 2 and 3, the titleproduct was obtained as a white solid.

1H NMR (CDCl₃, 400 MHz) δ 10.49 (1H, bs), 8.70 (1H, d, J=4.2 Hz), 7.99(1H, d, J=8.3 Hz), 7.57 (1H, dd, J=4.2, 8.7 Hz), 7.35 (1H,dd, J=5.0, 8.4Hz), 6.95(1H, dd, J=2.5,9.6Hz), 6.83 (1H, app. dt, J=2.6, 8.3Hz), 4.66(2H, J=5.9Hz), 4.38 (1H, dd, J=3.4, 14.7 Hz), 4.08 (1H, dd, J=6.6, 14.5Hz), 3.94 (1H, m), 3.92 (1H, d, J=10.3 Hz), 3.75-3.60 (4H, m), 3.43 (1H,dd, J=10.6, 11.8 Hz), 2.51 (3H, s) ppm.

C, H, N calc'd for C₂₂H₂₂FN₃O₅S C=57.51, H=4.83, N=9.15, found C=57.15,H=4.63, N=8.95.

EXAMPLE 61-(1,4-dioxan-2-ylmethyl)-N-[4-fluoro-2-(methylsulfonyl)benzyl]4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described for Examples 3 and 4, the titleproduct was obtained as a white foam.

¹H NMR (CDCl₃, 400 MHz) δ 10.8 (1H, bs), 8.70 (1H, d, J=4.4 Hz), 8.01(1H, d, J=8.9 Hz), 7.78 (1H, dd, J=2.8, 8.1 Hz), 7.69 (1H,dd, J=5.1, 8.4Hz), 7.59 (1H, dd, J=4.3, 8.8 Hz), 7.33 (1H, app. dt, J=2.5, 8.0 Hz),4.98 (2H, J=6.2 Hz), 4.42 (1H, dd, J=3.2, 14.7 Hz), 4.08 (1H, dd, J=6.5,14.5 Hz), 3.94 (2H, m), 3.75-3.55 (4H, m), 3.43 (1H, m) 3.25 (3H, s)ppm.

HRMS: calc'd for C₂₂H₂₂FN₃O₇S+1H=492.1235, observed 492.1219.

EXAMPLE 7N-(4-fluorobenzyl)-4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

Step 1: Preparation of benzyl 2-(methylamino)ethylcarbamate

To a solution of N-methyl ethylene diamine (10 g, 135 mmol) in CHCL₃(100 mL) was added TFA (11.43 mL, 148.4 mmol) and the solution wasstirred for several minutes. The reaction was then treated successivelywith 1-{[(benzyloxy)carbonyl]oxy)pyrrolidine-2,5-dione (Aldrich, 43.7 g,175.3 mmol) and 18-crown-6 (71.3 g, 269.8 mmol). The reaction becameslightly green. After stirring for 1 hour at room temperature, TLC(ninhydrin stain) showed no remaining starting amine. The reaction wastransferred to a separatory funnel and washed with KOH solution. Theaqueous layer was back-extracted several times. The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated to give 10 g of ayellow oil. The oil was dissolved in 300ml CHCl₃ and half of this volumewas chromatographed on silica (150 mm×7 inches, 1 Kg silica gel, packedin CHCl₃) eluting with CHCl₃ saturated NH₃. The pure fractions werecollected and the remaining half of the crude chromatographed in thesame way. Product fractions contaminated with some bis-CBZ protectedmaterial were dissolved in CHCl₃ and washed with acid water. The aqueouswas then basified and extracted with CHCl₃. The organic layer was driedover Na₂SO₄, filtered and concentrated with the other pure fractions togive the product as a clear, colorless oil.

¹H NMR (CDCl₃, 400 MHz) δ 7.3-7.4 (5H, m), 5.13 (2H, s), 3.35 (2H, bs),2.96 (3H, s), 2.85 (2H, bs), 1.25 (2H, bs).Step 2: Preparation of benzyl2-[methyl(methylsulfonyl)amino]ethylcarbamate

A solution of benzyl 2-(methylamino)ethylcarbamate (0.05 g, 0.24 mmol)in CH₂Cl₂ (5 mL was cooled to 6° C. and treated with triethylamine (0.1mL, 0.72 mmol) and methanesulfonyl chloride (0.02 mL, 0.24 mmol). Thereaction was warmed to room temperature and stirred overnight. Thereaction was washed with 10% KHSO₄, the organic layer was dried overNa₂SO₄, filtered and evaporated to give the product.

¹H NMR (CDCl₃, 400 MHz) δ 7.3-7.4 (5H, m), 5.23 (1H, bs), 5.10 (2H, s),3.4 (2H, m), 3.25 (2H, m), 2.88 (3H, s), 2.78 (3H, s).Step 3: Preparation of 2-[methyl(methylsulfonyl)amino]ethanaminiumchloride

A solution of benzyl 2-[methyl(methylsulfonyl)amino]ethylcarbamate (6.1g, 30.7 mmol) was treated with 6 N HCl (100 mL) and heated to 90° C. for1.5 hours then stirred at room temperature overnight. The solution wasextracted twice with ether and the aqueous layer was evaporated to givethe product as a sticky white solid that was taken on to the next step.

Rf (silica, 20% MeOH/CHCl₃/NH₃)=0.17Step 4: Preparation ofN-{2-[(2-cyanopyridin-3-yl)amino]ethyl}-N-methylmethanesulfonamide

In a manner similar to that described for Example 2,2-[methyl(methylsulfonyl)amino]ethanaminium chloride (4 g, 25.4 mmol)was dissolved in DMSO (20 mL) and treated with 3-fluoro-2-cyanopyridine(2.5 g, 21.2 mmol) and Hunig's base (4.4 mL, 25.4 mmol) and heated to 90degrees under pressure. The product was isolated as an oily off-whitesolid.

¹H NMR (CDCl₃, 400 MHz) δ 8.18 (1H, m), 7.38 (2H, m), 5.0 (1H, bs), 3.62(2H, m), 3.5 (2H, m), 3.05 (3H, s), 3.00 (3H, s).Step 5: Preparation of methyl4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]-ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate

In a manner similar to that described for Example 2,N-{2-[(2-cyanopyridin-3-yl)amino]ethyl}-N-methylmethanesulfonamide wastreated with MeOH, HCl and water to give methyl3-({2-[methyl(methylsulfonyl)amino]ethyl}-amino)pyridine-2-carboxylateafter aqueous workup. The crude product was then treated with NaH andmethyl 3-chloro-3-oxopropionate as described in Example 2 and afteraqueous workup the crude methyl4-hydroxy-1-{2-[methyl(methylsulfonyl)-amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylatewas obtained as a pink foam. A portion of the material was crystallizedfrom EtOH to give the product as light brown crystals.

¹H NMR (CDCl₃, 400 MHz) δ 8.67 (1H, d, J=4.3 Hz), 8.00 (1H, d, J=8.7Hz), 7.65 (1H, dd, J=4.3, 8.7 Hz), 4.44 (2H, m), 4.07 (3H, s), 3.43 (2H,m ), 2.96 (3H, s), 2.84 (3H, s).

Step 6: Preparation ofN-(4-fluorobenzyl)-4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Example 2, methyl4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylatewas dissolved in EtOH and treated with 4-fluorobenzylamine at reflux.After cooling the product fell out of solution and was collected. Thecrude was dissolved in CHCl₃, washed with 10% KHSO₄ solution, theorganic was dried over MgSO₄, filtered and evaporated to give theproduct as a white foam.

¹H NMR (CDCl₃, 400 MHz) δ 10.46 (1H, bs), 8.72 (1H, d, J=4.2 Hz), 8.02(1H, d, J=8.9 Hz), 7.65 (1H, dd, J=4.3, 8.7 Hz), 7.35 (2H, dd, J=5.5,8.3 Hz), 7.05 (2H, m), 4.63 (2H, d, J=6.0 Hz), 4.45 (2H, m), 3.39 (2H,m), 2.95 (3H, s), 2.84 (3H, s).

HRMS: calc'd for C₂₀H₂₁FN₄O₅S+1H=449.1289, observed 449.1266

EXAMPLE 8N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-{2-[methyl(methylsulfonyl)-amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described for Example 3, methyl4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate was dissolved inEtOH and treated at reflux with1-[4-fluoro-2-(methylthio)phenyl]methanamine. The crude product wasoxidized with m-CPBA as described for Example 3 to give the product as awhite foam.

¹H NMR (CDCl₃, 400 MHz) δ 10.76 (1H, bs), 8.72 (1H, d, J=4.2 Hz), 8.02(1H, d, J=8.9Hz), 7.78 (1H, dd, J=2.8, 8.2Hz), 7.72 (1H, dd, J=5.1, 8.6Hz), 7.65 (1H, dd, J=4.2, 8.8 Hz), 7.33 (1H, app. dt, J=2.8, 8.1 Hz),4.97 (2H, d, J=6.2 Hz), 4.47 (2H, m), 3.41 (2H, m), 3.24 (3H, s), 2.95(3H, s), 2.83 (3H, s).

HRMS: calc'd for C₂₁H₂₃FN₄O₇S₂+1H=527.1065, observed 527.1031.

EXAMPLE 91-[(1,1-Dioxidotetrahydrothien-3-yl)methyl]-N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Example 2,(1,1-dioxidotetrahydrothien-3-yl)methanaminium chloride (Chembridge) wastreated with 3-fluoro-2-cyano pyridine and then further derivatized togive the final compound.

¹H NMR (DMSO-d6, 400 MHz) δ 10.62 (1H, bs), 8.65 (1H, d, J=4.2 Hz), 8.24(1H, d, J=4.1 Hz), 7.78 (1H, dd, J=4.1, 8.6 Hz), 7.43 (2H, m), 7.19 (2H,m), 4.59 (2H, m), 4.40 (2H, m), 3.29, (1H, m), 3.23 (1H, m), 3.02 (2H,m), 2.80 (1H, m), 2.22 (1H, m)1.94 (1H, m).

C, H, N calc'd for C₂₁H₂₀FN₃O₅S 1.5 H₂O C=53.38, H=4.91, N=8.89, foundC=53.38, H=4.59, N=8.54.

EXAMPLE 10N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-[2-(methylsulfonyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described for Examples 2 and 3,2-(methylthio)ethanamine was reacted with 3-fluoro-2-cyanopyridine andthen derivatized to give the final product.

¹H NMR (CDCl₃, 400 MHz) δ 10.65 (1H, bs), 8.73 (1H, d, J=4.0 Hz), 7.92(1H, d, J=8.8 Hz), 7.78 (1H, dd, J=2.6, 8.2 Hz), 7.73 (1H, dd, J=5.1,8.4 Hz), 7.66 (1H, dd, J=4.3, 8.7 Hz), 7.34 (1H, app. dt, J=2.6, 8.1Hz), 4.56 (2H, d, J=6.3 Hz), 4.71 (2H, m), 3.43 (2H, m), 3.23 (3H, s),3.04 (3H, s).

HRMS: calc'd for C₂₀H₂₀FN₃O₇S₂+1Na+=520.0625, observed 520.0619.

EXAMPLE 111-ethyl-N-[4-fluoro-2-(methylthio)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Examples 2 and 3, ethylamine(1.3 equivalent of a 2.0 molar solution in THF) was treated with3-fluoro-2-cyanopyridine and then further derivatized to give theproduct.

¹H NMR (CDCl₃, 400 MHz) δ 10.60 (1H, bs), 8.71 (1H, d, J=4.3 Hz), 7.72(1H, d, J=8.7 Hz), 7.61 (1H, dd, J=4.2, 8.7 Hz), 7.36 (1H, dd, J=6.0,8.4 Hz), 6.96 (1H, dd, J=2.5, 9.5 Hz), 6.84 (1H, app. dt, J=2.5, 8.2Hz), 4.67 (2H, d, J=5.9 Hz), 4.30 (2H, q, J=7.1 Hz), 2.52 (3H, s), 1.34(3H, t, 7.1 Hz).

HRMS: calc'd for C₁₉H₁₈FN₃O₃S+1H=388.1126, observed 388.1138.

EXAMPLE 121-ethyl-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Examples 2 and 3, ethylamine(1.3. quivalents of a 2.0 molar solution in TH) was treated with3-fluoro-2-cyanopyridine and then further derivatized to give theproduct.

¹H NMR (DMSO, 400 MHz) δ 10.86 (1H, bs), 8.65 (1H, d, J=3.7 Hz), 8.15(1H, d, J=8.5 Hz), 7.79 (1H, dd, J=4.1, 8.6 Hz), 7.76-7.61 (3H, m), 4.94(2H, d, J 5.0 Hz), 4.29 (2H, q, J=6.4 Hz), 3.41 (3H, s), 1.21 (3H, t,6.8 Hz).

HRMS: calc'd for C₁₉H₁₈FN₃O₅S+1H=420.1024, observed 420.1037.

C, H, N calc'd for C₁₉H₁₈FN₃O₅S+0.5 EtoAc, C=54.42, H=4.70, N=9.24,observed C=54.7, H=4.92, N=9.24.

EXAMPLE 13N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Examples 2 and 3, methylamine(1.3 equivalents of a 2.0 molar solution in THE) was treated with3-fluoro-2-cyanopyridine and then further derivatized to give theproduct.

¹H NMR (DMSO, 400 MHz) δ 10.85 (1H, bs), 8.65 (1H, d, J=3.4 Hz), 8.10(1H, d, J=8.6 Hz), 7.80 (1H, dd, J=4.2, 8.6 Hz), 7.74 (1H, dd, J=2.8,8.6 Hz), 7.69 (1H, dd, J=5.5, 8.6 Hz), 7.69 (1H, app. dt, J=2.7, 8.4Hz), 4.94 (2H, d, J=6.0 Hz), 3.63 (3H, s), 3.41 (3H, s).

HRMS: calc'd for C₁₈H₁₆FN₃O₅S+1H=406.0867, observed 406.0868.

C,H,N calc'd for C₁₉H₁₈FN₃O₅S+0.05 H₂O+0.2 TFA, C=51.5, H=3.83, N=9.79,found C=51.55, H=3.88, N=9.4.

EXAMPLE 14N-(4-fluorobenzyl)-4-hydroxy-1-[2-(methylsulfinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Examples 2 and 3,2-(methylthio)ethanamine was treated with 3-fluoro-2-cyanopyridine andthen further derivatized to give the product.

¹H NMR (CDCl₃, 400 Mz) δ 10.38 (1H, bs), 8.76 (1H, d, J=4.3 Hz), 8.06(1H, d, J=8.7 Hz), 7.68 (1H, dd, J=4.2, 8.7 Hz), 7.34 (2H, dd, J=5.5,8.3 Hz), 7.05 (2H, t, J=8.6Hz), 4.76 (1H, m), 4.67 (1H, m), 4.63 (2H, d,J=5.7 Hz), 3.18 (1H, m), 3.05 (1H, m), 2.71 (3H, s).

HRMS: calc'd for C₁₉H₁₈FN₃O₄S+1H=404.1080, observed 404.1073.

C, H, N calc'd for C₁₉H₁₈FN₃O₄S+0.55 TFA, C=51.79, H=4.01, N=8.86, foundC=51.70, H=3.90, N=8.86.

EXAMPLE 15N-(4-fluorobenzyl)-4-hydroxy-1-[2-(methylsulfonyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Examples 2 and 3,2-(methylthio)ethanamine was treated with 3-fluoro-2-cyanopyridine andthen further derivatized to give the product.

¹H NMR (CDCl₃, 400 MHz) δ 10.34 (1H, bs), 8.75 (1H, dd, J=1.1, 4.3 Hz),7.92 (1H, d, J=8.8 Hz), 7.68 (1H, dd J=4.3, 8.7 Hz), 7.35 (2H, m), 7.07(2H, t, J=8.7 Hz), 4.69 (2H, t, J=7.4 Hz), 4.63 (2H, d, J=5.8 Hz), 3.42(2H, t, J=7.4 Hz), 3.03 (3H, s).

HRMS: calc'd for C₁₉H₁₈FN₃O₅S+1H=420.1029, observed 404.1024.

C, H, N calc'd for C₁₉H₁₈FN₃O₅S+0.1 TEA, C=53.53, H=4.23, N=9.75, foundC=53.66,1H=3.81, N=9.47.

EXAMPLE 16N-(4-fluorobenzyl)-4-hydroxy-1-(2-morpholin-4ylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described for Examples 2 and 3,2-morpholin-4-ylethanamine (Aldrich) was reacted with 3-fluoro-2-cyanopyridine and further derivatized to give the product.

¹H NMR (DMSO-d6, 400 MHz) δ 10.56 (1H, bs), 9.68 (1H, bs), 8.71 (1H, d,J=4.2 Hz), 8.17 (1H, d, J=9.0 Hz), 7.77 (1H, dd, J=4.2, 8.8Hz), 7.43(2H, m), 7.21(2H, m), 4.62 (4H, m), 4.01 (4H, m), 3.63 (2H, m), 3.43(2H, m), and 3.21 (2H, m) ppm.

APCI Exact Mass: Measured Mass [M+1]=427.1796, Theorectical Mass[M+1]=427.1776

EXAMPLE 17N-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(1H-1,2,4-triazol-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide,trifluoroacetic acid salt

In a manner similar to that described for Examples 2 and 3,2-(1H-1,2,4-triazol-1-yl)ethanaminium hydrogen sulfate (ChembridgeCorp.) was reacted with 3-fluoro-2-cyano pyridine and furtherderivatized to give the product.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.51 (1H, bs), 8.60 (1H, d, J=4.2 Hz), 8.45(1H, s), 7.89 (1H, s), 7.79(1H, d, J=8.8 Hz), 7.66 (1H, dd, J=4.2, 8.8Hz), 7.44 (2H, m), 7.21(2H, m), 4.64 (2H, t, J=5.68), 4.59 (2H, d,J=5.67), and 4.53 (2H, m) ppm.

APCI Exact Mass: Measured Mass [M+Na]=431.1239, Theorectical Mass[M+Na]=431.1238

EXAMPLE 181-[2-(dimethylamino)-2-oxoethyl]-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

Step 1: Preparation of methyl4-hydroxy-1-(2-methoxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate

In a manner similar to that described in Example 2, glycine methyl esterhydrochloride was reacted with 3-fluoro-2-cyanopyridine. As described inExample 2, the resulting cyano compound was treated under Pinnerconditions to give the ester, which was reacted with methyl3-chloro-3-oxo propionate to give the product as a sticky orange solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.62 (1H, d), 8.31 (1H, s), 8.04 (1H, d),7.74 (1H, dd), 5.06 (2H, s), 3.79 (3H, s), 3.70 (3H, s) ppm.Step 2: Preparation of methyl[3-({[4-fluoro-2-(methylthio)benzyl]amino}carbonyl)-4-hydroxy-2-oxo-1,5-naphthyridin-1(2H)-yl]acetate

In a manner similar to that described in Example 2, methyl4-hydroxy-1-(2-methoxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylatewas treated with 1-[4-fluoro-2-(methylthio)phenyl]methanamine in EtOH at80° C. for 48 hours. The reaction was cooled and the solid percipitatecollected and washed with EtOH to give the product as a white solid.

ESMS: calc'd 431.4, observed 431.9 (M+1).Step 3: Preparation of methyl[3-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}carbonyl)-4-hydroxy-2-oxo-1,5-naphthyridin-1(2H)-yl]acetate

In a manner similar to that described in Example 3, methyl[3-({[4-fluoro-2-(methylthio)benzyl]amino}carbonyl)4-hydroxy-2-oxo-1,5-naphthyridin-1(2H)-yl]acetatewas treated with m-chloroperoxybenzoic acid and after purification onreverse phase HPLC was isolated as a light yellow solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.58 (1H, bs), 8.66 (1H, d, J=4.0 Hz), 8.10(1H, d, J=8.6 Hz), 7.78 (1H, dd, J=4.0, 8.4 Hz), 7.73 (1H, dd, J=2.6,8.6 Hz), 7.67 (1H, dd, J=5.5, 8.7 Hz), 7.62 (1H, app. dt, J=2.6, 8.3Hz), 5.13 (2H, bs), 4.92 (2H, d, J=5.9 Hz), 3.70 (3H, s), 3.4 (3H, s).Step 4: Preparation of[3-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}-carbonyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridin-1(2H)-yl]aceticacid

A suspension of methyl[3-({[4-fluoro-2-(methylsulfonyl)benzyl]-amino}carbonyl)-4-hydroxy-2-oxo-1,5-naphthyridin-1(2H)-yl]acetate(77mg, 0.166 mmol) in 3N NaOH (0.55 mL) was heated to reflux for onehour. The solution was poured into 10% KHSO₄ and extracted four timeswith EtOAc. The organic layer was dried over Na2SO4, filtered andconcentrated to give the product as a white solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 13.1 (1H, bs), 10.64 (1H, bs), 8.66 (1H,bs,), 8.07 (1H, d, J=8.6 Hz), 7.8 (1H, m), 7.74 (1H, m), 7.7 (1H, m),7.62 (1H, m), 5.04 (2H, bs), 4.93 (2H, d, J=5.4 Hz), 3.41 (3H, s) ppm.

Step 5: Preparation of1-[2-(dimethylamino)-2-oxoethyl]-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate.

Dry DMP (0.5 mL) was saturated with dimethylamine gas and[3-({[4-fluoro-2-(methylsulfonyl)benzyl)amino}carbonyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridin-1(2H)-yl]aceticacid (0.40 g, 0.089 mmol) and triethylamine ( 0.025 mL, 0.178 mmol), andBOP reagent (0.051 g, 0.116 mmol) were added. The reaction was stirredat room temperature, re-saturated with dimethylamine after 1 hour andstirred overnight. The crude reaction product was purified on reversephase HPLC eluting with 5:95% acetonitrile/water (0.1% TFA) to 95:5% togive the product as a light yellow solid.

¹HNMR (DMSO-d₆, 400 MHz) δ 10.68 (1H, bs), 8.64 (1H, d, J=4.2 Hz), 7.94(1H, d, J=8.8 Hz), 7.76-7:60 (4H, m), 5.19 (2H, m), 4.93 (2H, m), 3.40(3H, s), 3.15 (3H, s ), and 2.85 (3H, s) ppm.

ESMS Exact Mass: C₂₁H₂₁FN₄O₆S Measured Mass [M+1]=477.1215, TheoreticalMass [M+1]=477.1239

EXAMPLE 19N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

The compound was prepared in a manner similar to that described forExamples 1 and 3.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.99 (1H, bs), 10.79 (1H, bs), 8.58 (1H, d,J=2.2 Hz), 7.77-7.68 (5H, m), 4.94 (2H, d, J=5.7 Hz), and 3.40 (3H, s)ppm.

ESMS Exact Mass: Measured Mass [M+1]=392.0711, Theorectical Mass[M+1]=392.0711

EXAMPLE 20N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-(2-methoxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Examples 2 and 3,2-(methoxyethyl)methanamine was reacted with 3-fluoro-2-cyanopyridineand then further derivatized to give the product.

¹H NMR (CDCl₃, 400 MHz) δ 10.88 (1H, bs), 8.67 (1H, d, J=4.3 Hz) 8.00(1H, d, J=8.8 Hz), 7.79 (1H, m), 7.70 (1H, dd, J=5.2, 8.4 Hz), 7.57 (1H,m), 7.33 (1H, m) 4.98 (2H, d, J=6.22 Hz), 4.44 (2H, m), 3.73 (2H, m),3.29 (3H, s), 3.25 (3H, s) ppm.

ESMS Exact Mass: Measured Mass [M+1]=450.1127, Theorectical Mass[M+1]=450.1135.

EXAMPLE 21 1-Benzyl-n-[4-fluoro-2-(methylsulfonyl)benzyl]hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

In a manner similar to that described in Examples 2 and 3, benzylaminewas reacted with 3-fluoro-2-cyanopyridine and then further derivatizedto give the product.

¹H NMR (CDCl₃, 400 MHz) δ 10.89 (1H, bs), 8.67 (1H, d, J=4.2 Hz) 7.77(1H, dd, J=2.8, 8.2 Hz), 7.71 (1H, dd, 5.1, 8.6 Hz), 7.60 (1H, d, J=8.7Hz), 7.46 (1H, dd, J=4.3, 8.7 Hz), 7.28-7.36 (4H, m), 7.15 (2H, d,J=7.14 Hz), 5.52 (2H, s), 5.00 (2H, d, J=6.2 Hz), 3.23 (3H, s)ppm.

ESMS Exact Mass: Measured Mass [M+1]=482.1178, Theoretical Mass[M+1]=482.1186.

EXAMPLE 221-{2-[[(dimethylamino)sulfonyl](methyl)amino]ethyl}-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

Step 1: Preparation of benzyl2-[(2-cyanopyridin-3-yl)amino]ethyl(methyl)carbamate

A solution of benzyl 2-(methylamino)ethylcarbamate (prepared asdescribed in example 7, 14 g, 72.1 mmol) in DMSO (20 mL) was reactedwith 3-fluoro-2-cyanopyridine (see example 2, 8 g, 65.5 mmol) in apressure vessel at 85° C. overnight. The resulting mixture was dilutedwith CHCl3 (100 mL) and added to the top of a silica gel column (150 mmby 7 inches) packed with 20% EtOAc/Hexanes. The column was eluted with agradient of 20% EtOAc/Hexanes to 100% EtOAc and the clean fractionscombined and evaporated to give the product as a yellow oil.

¹H NMR (CDCl₃, 400 MHz) δ 7.97(1H, bs), 7.4-7.3 (5H, m), 7.15 (1H, m),7.03 (1H, bs), 6.85 (1H, m), 5.17 (2H, s), 3.55 (2H, m), 3.40 (2H, m),2.99 (3H, s) ppm.Step 2: Preparation of methyl3-{[2-(methylamino)ethyl]amino}pyridine-2-carboxylate

In a manner similar to that described in example 2, benzyl2-[(2-cyanopyridin-3-yl)amino]ethylcarbamate (11.9 g, 38.3 mmol) wasdissolved in MeOH and treated with HCl gas and water to give the ester.The reaction was concentrated, dissolved in MeOH and adsorbed to silicagel. The product was eluted with CHCl3 saturated with NH3, the fractionswere collected and evaporated to give the product as a yellow oil thatcrystallized upon sitting.

¹H NMR (CDCl₃, 400 MHz) δ 8.0 (1H, dd, J=0.8,4.2 Hz), 7.88 (1H, bs),7.27 (1H, dd, buried, J=4.2Hz), 7.11 (1H, d, J=8.4Hz), 3.96 (3H, s),3.32 (2H, m), 2.90 (2H, m), 2.49 (3H, s) ppm.Step 3: Preparation of methyl3-[(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]pyridine-2-carboxylate

A solution of methyl 3-[(2-aminoethyl)amino]pyridine-2-carboxylate (3.9g, 18.6 mmol) in CHCl₃ (25 mL) was treated with pyridine (3 mL, 37.3mmol) then 1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (Aldrich,5.57 g, 22.3 mmol) for ½ hr. The reaction was quenched with water andextracted three times with CHCl3. The organic layer was dried withNa₂SO₄, filtered and evaporated to give an oil. The crude was purifiedon silical gel using an ISCO normal phase system and eluting with agradient of 50% to 90% EtOAc Hexanes. The clean fractions were combinedto give the product as an oil.

¹H NMR (CDCl₃, 400 MHz) δ 8.0 (1H, bd, J=12.72 Hz), 7.84 (1H, bs), 7.36(5H, bs), 7.26 (1H, bs), 7.02-6.95 (1H, m), 5.16 (2H, s), 3.94 (3H, s),3.4-3.28 (4H, m), 3.0 (3H, s) ppm.Step 4: Preparation of methyl1-{2-[[(benzyloxy)carbonyl](methyl)amino]-ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate

In a manner similar to that described for example 2, methyl3-[(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]pyridine-2-carboxylate wastreated with NaH and methyl 3-chloro-3-oxopropionate. After aqueousworkup, the resulting oil was triturated with ether and CH₂Cl₂ to givethe product as an off-white solid. More product was obtained fromreverse phase HPLC purification of the mother liquor.

¹H NMR (DMSO-d6, 400 MHz) δ 8.23 (1H, m), 7.5 (1H,m), 7.4-7.25 (5H, m),7.1 (1H,m), 5.06 (1H, s), 4.99 (1H, s), 4.2 (2H, bs), 3.6 (3H, s), 3.38(2H, bs), 2.86 (3H, s) ppm.Step 5: Preparation of 4-fluoro-2-(methylthio)benzonitrile.

2,4-difluorobenzonitrile (2.0 g, 14.38 mmol) and thiomethoxide (1.02 g,14.38 mmol) were placed in an oven dried 100 mL round bottom flaskfitted with a reflux condenser. Toluene (40 mL) was added and thereaction solution was put under an atmosphere of Argon. The reaction washeated to 90° C. over 48 hours. The crude reaction was cooled andconcentrated in vacuo. The residue was taken up in methylene chlorideand extracted with water. The organic phase was dried (MgSO₄), filteredand concentrated to afford a white solid. The solid was dissolved in aminimal amount of methylene chloride and purified on an ISCO column (110g silica) with a gradient of 100% to 80% hexanes/20% ethylacetate over15 min at 45 ml/min, then 20% EtOAc/80% Hexanes for 5 min. The collectedfractions were evaporated in vacuo to afford the desired material in a7.5:1 ratio 4-fluoro-2-(methylthio)benzonitrile:2-fluoro-4-(methylthio)benzonitrile. The white solid was carried on tothe next step without further purification.

¹H NMR (CDCl₃, 400 MHz, major regioisomer) δ 7.56 (1H, dd, J=5.58, 8.51Hz), 6.95 (1H, dd, J=2.38, 9.34 Hz), 6.88 (1H, dt, J=2.38, 8.24 Hz),2.54 (3H, s) ppm.

EI HRMS exact mass calc'd for C₈H₆FNS 167.0203, found 167.0205Step 6: Preparation of 4-fluoro-2-(methylsulfonyl)benzonitrile.

4-fluoro-2-(methylthio)benzonitrile (1.59 g, 9.51 mmol, 7.5:1 mixture ofregioisomers from Step 1) was dissolved in methylene chloride (50 mL)and 3-chloroperoxybenzoic acid (60% by weight, 4.6 g, 16 mmol) wasadded. The reaction was put under an atmosphere of Argon and stirredovernight at ambient temperature. The reaction was quenched withsaturated aqueous sodium bicarbonate (2×100 mL). The organic phase stillcontained some 3-chloroperoxybenzoic acid by LCMS analysis so 1 mL DMSOwas added and stirred for 1 hour. The organic phase was then extractedagain with saturated aqueous sodium bicarbonate (100 mL), dried (MgSO4),filtered and concentrated to afford the desired material as a 7:1 ratioof4-fluoro-2-(methylsulfonyl)benzonitrile:2-fluoro-4-(methylsulfonyl)-benzonitrile.Selective crystallization from methanol, filtration and drying in vacuoafforded the desired 4-fluoro-2-(methylsulfonyl)benzonitrile as whitecrystals.

¹H NMR (CDCl₃, 400MHz, major regioisomer) δ 7.93 (1H, dd, J=4.77, 8.51Hz), 7.90 (1H, dd, J=2.36, 7.70 Hz), 7.45 (1H, ddd, J=2.56, 7.24, 8.47Hz), 3.28 (3H, s) ppm.

EI HRMS exact mass calc'd for C₈H₆FNSO₂ 199.0103, found 199.0103Step 7: Preparation of1-[4-fluoro-2-(methylsulfonyl)phenyl]methanaminium chloride

4-fluoro-2-(methylsulfonyl)benzonitrile (5.6 g, 28.11 mmol) was added toa dry Parr bottle. Methanol (50 mL) and conc HCl (10 mL) were added andthe reaction solution put under an Argon atmosphere. 10% Pd/C (1 gram)was added and the reaction vessel placed on a Parr hydrogenationapparatus. The reaction was placed under an atmosphere of H₂ (50 psi)and shaken overnight. After overnight the ratio of starting material toproduct was 50:50. The reaction was filtered through celite andconcentrated slightly. Conc. HCl (10 mL) and 10% Pd/C (1 gram) wereadded and the reaction was again put under H₂ (50 psi). The reaction wasagain shaken overnight. The crude reaction was filtered through celiteand concentrated to afford the desired material as a white solid.

¹H NMR (CDCl₃, 400MHz) δ 7.86 (1H, dd, J=2.74, 8.24 Hz), 7.74 (1H, dd,J=5.03, 8.51 Hz), 7.57 (1H, dt, J=2.75, 8.15 Hz), 4.45 (2H, s), 3.27(3H, s) ppm.

MS calc'd for C₈H₁₀FNO₂S 203 (MH+), found 204.

EI HRMS exact mass calc'd for C₈H₁₀FNO₂S 203.0410, found 203.0416

C,H,N calc'd for C₈H₁₀FNO₂S 1.1 HCl % C 39.49, % H 4.6, % N 5.76, found% C 39.50, % H 4.34, % N 5.56Step 8: Preparation of benzyl2-[3-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}carbonyl)-4-hydroxy-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl(methyl)carbamate

A solution of methyl1-{2-[[(benzyloxy)carbonyl](methyl)amino]-ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(0.5 g, 1.21 mmol) in MeOH (6mL) was treated with Hunig's base (0.33 mL,1.82 mmol) and 1-[4-fluoro-2-(methylsulfonyl)phenyl]methanaminiumchloride (0.35 g, 1.46 mmol) and heated in a sealed reaction vessel at80 degrees C. After overnight, an additional 0.5 equivalents of theamine and 1.5 equivalents of Hunig's base was added and the reactionheated until HPLC showed the starting material gone. The reaction wascooled and the solids that percipitated were collected by filtration togive pure product.

¹H NMR (DMSO-d6, 400 MHz) δ 11.2 (1H, bs), 8.3 (1H, bd), 7.9 (1H, m),7.85 (1H, m), 7.65 (2H, m), 7.55(1H, m 7.48 (1H, m), 7.3 (4H, m), 7.1(1H, m), 5.05 (1H, s), 4.95 (1H, s), 4.8(2H, bs), 4.2 (2H, bs), 3.4 (3H,s), 3.4 (3H, s), 2.88 (2H, bs) ppm.Step 9: Preparation ofN-[4-fluoro-2-(methylsulfonyl)benzyl]4-hydroxy-1-[2-(methylamino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

A solution of benzyl2-[3-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}-carbonyl)-4-hydroxy-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl(methyl)carbamate(0.55 g, 0.94 mmol) in MeOH (10 mL) in a pressure tube was cooled to −78degrees C. and saturated with HCl gas. The volume in the flask visiblyincreased. The reaction was allowed to warm to room temperatureovernight, then cooled to −78 degrees C. and vented. The reaction wastransferred to a round bottom flask and the solvents removed undervacuum. The reaction was suspended in toluene and evaporated to give theproduct as a solid.

¹H NMR (DMSO-d6, 400 MHz) δ 10.7 (1H, m), 9.2-9.1 (1H, m), 8.67 (1H, d,J=4.2 Hz), 8.40 (1H, d, J=8.5 Hz), 7.80 (1H, dd, J=4.3, 8.7 Hz), 7.6-7.2(2H, m), 7.63 (1H, app t, J=2.7, 8.5 Hz), 4.95 (2H, d, J=5.8 Hz), 4.6(2H, m), 3.41 (3H, s), 3.16 (2H, bs), 2.56 (3H, bs) ppm.

Step 10: Preparation of1-{2-[[(dimethylamino)sulfonyl](methyl)amino]ethyl}-N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide.

A solution ofN-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-[2-(methylamino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide(0.07 g, 0.16 mmol) in DM (3 mL) was treated with dimethylsulfamoylchloride (0.44 g, 0.31 mmol) and Hunig's base (0.11 mL, 0.62 mmol) andstirred at room temperature for several hours. Additionaldimethylsulfamoyl chloride was added after an hour. The reaction wasinjected directly onto a reverse phase HPLC column and the compoundcollected after eluting with a gradient of 95% water/acetonitrile to 5%water acetonitrile. The fractions were combined, evaporated and thecrude oil was lyophilized from acetonitrile and water to give theproduct as a fluffy solid.

¹H NMR (CDCl₃, 400 MHz) δ 10.77 (1H, m), 8.72 (1H, d, J=4.2 Hz), 8.07(1H, d, J=8.6 Hz), 7.77 (1H, dd, J=2.7, 8.2 Hz), 7.70 (1H, dd, J=5.1,13.3 Hz), 7.66 (1H, dd, J=4.3, 8.8 Hz), 7.33 (1H, app dt, J=2.7, 8.0Hz), 4.98 (2H, d, J=6.2 Hz), 4.48 (2H, m), 3.45 (2H, m), 3.24 (3H, s),2.94 (3H, s), 2.79 (6H, s) ppm.

ESMS Exact Mass: Measured Mass [M+1]=556.1325, Theoretical Mass[M+1]=556.1330.

EXAMPLE 23N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

The compounds was prepared in a manner similar to that described forExample 18.

¹H NMR (DMSO-d6, 400 MHz) δ 10.6 (1H, bs), 9.88 (1H, bs), 8.65 (1H, d,J=4.2 Hz), 7.94 (1H, d, J=8.97 Hz), 7.8-7.7 (3H, m), 7.64 (1H, m), 5.4(1H, d, J=16.4 Hz), 5.16 (1H, d, J=16.4 Hz), 4.91 (2H, d, J=6.0 Hz), 4.3(2H, m), 3.5 (8H, m), 3.2 (1H, m), 3.0 (1H, m), 2.88 (3H, s).

ESMS Exact Mass: Measured Mass [M+1]=532.1652, Theoretical Mass[M+1]=532.1661.

EXAMPLE 24N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-(2-morpholin-4-yl-2-oxoethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

The compounds was prepared in a manner similar to that described forExample 18.

1H NMR (DMSO-d6, 400 MHz) δ 10.68 (1H, m), 8.64 (1H, d, J=4.2 Hz), 7.93(1H, d, J=8.6 Hz), 7.78-7.59 (4H, m), 5.23 (2H, s), 4.92 (2H, d, J=6.2Hz), 3.7 (2H, bs), 3.6-3.4 (6H, m), 3.40 (3H, s) ppm.

ESMS Exact Mass: Measured Mass [M+1]=519.1338, Theoretical Mass[M+1]=519.1344.

EXAMPLE 25N-[4-fluoro-2-(methylsulfonyl)benzyl]-1-{2-[[(dimethylamino)carbonyl](methyl)-amino]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

The compound was prepared in a manner similar to that decribed forExample 22, usingN-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-[2-(methylamino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamideand N,N-dimethylcarbamoyl chloride.

¹H NMR (CDCl₃, 400 MHz) δ 10.8 (1H, m), 8.72 (1H, d, J=3.74 Hz) 8.42(1H, d, J=8.7 Hz), 7.77 (1H, dd, J=2.7, 8.1 Hz), 7.71(2H, m), 7.33 (1H,app t, J=2.7, 8.1 Hz), 4.87 (2H, d, J=6.3 Hz), 4.49 (2H, m), 3.35 (2H,m), 3.25 (3H, s), 3.02 (3H, s), 2.85 (6H, s).

ESMS Exact Mass: Measured Mass [M+1]=520.1642, Theoretical Mass[M+1]=520.1661.

EXAMPLE 261-Benzyl-N-{4-fluoro-2-[(methylamino)carbonyl]benzyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

Step 1: Methyl 2-(bromomethyl)-5-fluorobenzoate

With no precautions to maintain a dry atmosphere, methyl5-fluoro-2-methylbenzoate (Maybridge, 5 g, 29.7 mmole) was dissolved inCCl4 (50 mL). N-bromosuccinimide (5.82 g, 32.7 mmol) and benzoylperoxide (0.36 g, 1.48 mmole) were added and the reaction brought toreflux overnight. An additional 0.3 eq of NBS and 0.01 eq of benzoylperoxide was added and the reaction refluxed for 4 hrs, then cooled,filtered and concentrated. The residue was chromatographed on silicaeluting with a gradient of 0-10% EtOAc/Hexanes. The fractions werecollected to give the product, which was a mixture of mono andbis-brominated materials, as a clear oil.

¹H NMR (CDCl₃, 400 MHz, major product peaks) δ 7.67 (1H, dd, J=2.8, 9Hz), 7.45 (1H, dd, J=5.4, 9 Hz), 7.20 (1H, m), 4.93 (2H, s), 3.95 (3H,s) ppm.Step 2: Methyl2-{[bis(tert-butoxycarbonyl)amino]methyl}-5-fluorobenzoate

In a dry flask under nitrogen, di-tert-butyl iminodicarboxylate(Aldrich, 3.86 g, 17.8 mmol) was dissolved in dry DMF (5 mL) and treatedwith NaH (60% dispersion in oil, 0.71 g, 17.8 mmol). After the evolutionof gas had ceased, Methyl 2-(bromomethyl)-5-fluorobenzoate (4 g, 16.2mmole) dissolved in DMF (5 mL) was added. An additional 5 mL of DMF wasadded to aid stirring. The reaction was stirred for 2 hrs, thenpartitioned between water and EtOAc. The organic layer was dried withNa2SO4, filtered and concentrated and the residue was purified on silicaeluting first with toluene, then with a gradient of 0-5% MeOH/CHCl3. Theimpure product thus obtained was re-chromatographed on silica elutingwith a gradient of 0-30% EtOAc/Hexanes. The product was obtained as aclear oil.

¹H NMR (DMSO, 400 MHz,) δ 7.63 (1H, dd, J=2.8, 9.4 Hz), 7.52 (1H, m),7.20 (1H, dd, J=5.3, 8.7 Hz), 4.98 (2H, s), 3.86 (3H, s), 1.38 (s, 18H)ppm.Step 3: Preparation of tert-butyl4-fluoro-2-[(methylamino)carbonyl]-benzylcarbamate

A solution of methyl2-{[bis(tert-butoxycarbonyl)amino]methyl}-5-fluorobenzoate (5.0 g, 13.04mmol) in toluene (40 mL) was treated with methyl amine gas at −78° C.until the solution was saturated. The reaction contents were then placedinto a steel bomb and heated to 70° C. overnight. After cooling, thereaction was concentrated and then the solids were triturated withether. The resulting solids were collected by vacuum filtration. As aresult of the relatively harsh reaction conditions one of the BOCprotecting groups was removed from the molecule.

¹H NMR (CDCl₃, 400 MHz) δ 7.41 (1H, dd, J=5.6, 8.3 Hz), 7.14-7.06 (2H,m), 6.64 (1H, bs), 5.69 (1H, bs), 4.26 (2H, d, J=6.3 Hz), 2.98 (3H, d,J=4.8 Hz), 1.41 (9H, s) ppm.Step 4: Preparation of{4-fluoro-2-[(methylamino)carbonyl]phenyl}-methanaminium chloride

A solution of tert-butyl4-fluoro-2-[(methylamino)carbonyl]-benzylcarbamate (2.59 g, 9.17 mmol)in EtOAc (75 mL) was cooled to −78° C. After cooling solids precipitatedout of the solution. HCl gas was added to the suspension until itreached saturation at which time the reaction became homogenous. Afteradding the HCl gas the dry ice bath was replaced with an ice water bathand the reaction was stirred for 10 minutes at 0° C. The solution wasconcentrated slowly and then redissolved in EtOAc and this was repeatedtwo more times. The resulting solids were then triturated from EtOAc andfluffy white solids were collected by vacuum filtration.

¹H NMR (DMSO, 400 MHz) δ 8.82 (1H, d, J=4.2 Hz), 8.34 (3H, bs), 7.64(1H, dd, J=5.6, 8.5 Hz), 7.49-7.41 (2H, m), 4.04 (2H, s), 2.80 (3H, d,J=4.5 Hz) ppm.

The above compound({4-fluoro-2-[(methylamino)carbonyl]phenyl}-methanaminium chloride) mayalso be prepared in other ways, one of which is the following:4-fluoro-2-iodo-1-methylbenzene (Maybridge) may be brominated asdescribed for step 1 in the above scheme to give1-(bromomethyl)-4-fluoro-2-iodobenzene, and then treated withdi-tert-butyl iminodicarboxylate to givedi(tert-butyl)4-fluoro-2-iodobenzylimidodicarbonate. This iodide canthen be carbonylated by heating it under pressure with carbon monoxide,dppf, Pd(OAc)₂, an amine base like diisopropylethylamine and a greatexcess of methylamine in a solvent like DMF to give di(tert-butyl)4-fluoro-2-[(methylamino)carbonyl]benzylimidodicarbonate containing somemono (tert-butyl) imidodicarbonated material. This mixture can then betreated with HCl gas in a solvent like Ethyl Acetate at cold temperatureto remove the (tert-butyl) imidodicarbonate group(s), giving{4-fluoro-2-[(methylamino)-carbonyl]phenyl}methanaminium chloride.Step 5: Preparation of methyl4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (bis sodiumsalt)

To a solution of methyl3-[(3-methoxy-3-oxopropanoyl)amino]-pyridine-2-carboxylate (7.3 g, 29.9mmol, prepared as described in example 1) in anhydrous TBF (100 mL) wasadded solid sodium methoxide (3.9 g, 72.4 mmol) at 0° C. Immediatelyfollowing the addition of the sodium methoxide, solids crashed out ofthe solution. The ice bath was then removed and the suspension wasstirred for an additional 0.5 hours. The suspension was then filteredthrough a medium porosity filtration funnel to afford yellow solids.

¹NMR (D₂0, 400 MHz) δ 8.17 (1H, d, J=4.4 Hz), 7.38 (1H, d, J=8.4 Hz),7.26 (1H, dd, J=4.4, 8.4 Hz), 3.72 (3H, s) ppm.Step 6: Preparation of methyl1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate

To a solution of the sodium salt of methyl4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (2.0 g, 7.57mmol) in water (50 mL) was added a solution of benzyl bromide (3.89 g,22.72 mmol) in methylene chloride (50 mL). To the biphasic solution wasthen added tetrabutylammonium bromide (1.2 g, 3.79 mmol) and thereaction was sealed and heated to 50° C. After stirring overnight thereactions was cooled and the two layers were separated. The aqueouslayer was extracted one time with methylene chloride and the combinedorganics were dried over sodium sulfate, filtered and concentrated. Thecrude mixture was separated by normal phase chromatography using an Isco120 gram silica gel cartridge with a 50 minute gradient running at 40mL/min. of 10% to 60% EtOAc/hexanes. The tubes containing the desiredproduct were concentrated and taken on to the next step.

¹NMR (CDCl3, 400 M) δ 8.55 (1H, m), 7.59 (1H, d, J=8.7 Hz), 7.48 (2H, d,J=7.3 Hz), 7.37-7.16 (9H, m), 5.69 (2H, s), 5.46 (2H, s), 3.87 (3H, s)ppm.

MS calc'd for C₂₄H₂₀N₂O₄ 400(M), found 401 (MH+)Step 7: Preparation of1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylicacid

To a solution of methyl1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydro-1,5naphthyridine-3-carboxylate(0.65 g, 1.62 mmol) in THF (20mL) was added sodium hydroxide (16.2 mL, 1N) and the solution was heated to 80° C. and after 1.5 hours thereaction was completed. The reaction was allowed to cool and then theTHF was removed leaving the product in water. The water was acidifiedwith 1N HCl to adjust the pH to 3 and the resulting crude solids werecollected by vacuum filtration and taken on as is.

MS calc'd for C₂₃H₁₈N₂O₄ 386(M), found 387 (MH+)Step 8: Preparation of1-benzyl4-(benzyloxy)-N-{4-fluoro-2-[(methylamino)carbonyl]benzyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide

To a solution of1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylicacid (0.15 g, 0.39 mmol) in DMF (4 mL) was added HOAT (0.26 g, 1.94mmol) and EDC (0.07 g, 0.47 mmol). The solution was stirred for 10minutes at which time EDC (0.036 g, 0.23 mmol),{4-fluoro-2-[(methylamino)carbonyl]phenyl}methanaminium chloride (0.108g, 0.47 mmol), and DIEA (0.10 g, 0.78 mmol) were added. The reaction wasthen stirred at room temperature overnight at which time the solutionwas purified by preparative reverse phase “PLC eluting with a gradientof 5-95% acetonitrile/water (0.1% TFA). The fractions that contained thedesired product were concentrated. Note that during the prepdes-O-benzyl product was also obtained. The mixture was taken on to thenext step.

¹NMR (CDCl3, 400 MHz) δ 8.59 (1H, d, J=3.9 Hz), 7.69 (1H, t, J=5.7 Hz),7.59 (2H, d, J=8.3 Hz), 7.50 (2H, dd, J=5.5, 8.5 Hz), 7.40 (1H, dd,J=4.4, 8.6 Hz), 7.37-7.28 (6H, m), 7.18-7.12 (4H, m), 7.03 (1H, dt,J=2.7, 8.3 Hz), 5.23 (2H, s), 5.48 (2H, s), 4.59 (2H, d, J=5.8 Hz), 2.94(3H, d, J=4.6 Hz) ppm.

MS calc'd for C₃₂H₂₇FN₄O₄ 550(M), found 551 (MH+)

Step 9: Preparation of sodium1-benzyl-3-[({4-fluoro-2-[(methylamino)carbonyl]benzyl}amino)carbonyl]-2-oxo-1,2-dihydro-1,5-naphthyridin-4-olate

To a solution of1-benzyl-4-(benzyloxy)-N-{4-fluoro-2[(methylamino)carbonyl]benzyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide(0.06 g, 0.11 mmol) in methylene chloride (3 mL) was added TFA (1 mL)The reaction was stirred for 5 minutes at room temperature and thenconcentrated. The residue was redissolved in a minimum of DMF andpurified by preparative reverse phase BPLC eluting with a gradient of5-95% acetonitrile/water (0.1% TFA). The fractions that contained thedesired product were concentrated. The solids were dissolved in a 50:50mixture of CH₃CN/acetone followed by the addition of 1 N NaOH (0.109mL). The solution was stirred for 0.5 hours and then concentrated toafford yellow solids.

¹NMR (DMSO, 400 MHz) δ 11.20 (1H, d, J=5.5 Hz), 8.68 (1H, d, J=4.2 Hz),8.28 (1H, d, J=5.8 Hz), 7.51-7.47 (2H, m), 7.23 (1H, dd, J=4.2, 8.4 Hz),7.29-7.16 (7H, m), 5.38 (2H, bs), 4.53 (2H, d, J=5.8 Hz), 2.78 (3H, d,J=4.4 Hz) ppm.

High resolution MS calc'd for C₂₅H₂₁FN₄O₄ 461.1620(MH+), found 461.1619(MH+)

EXAMPLE 27N-[4-Fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-l-(2-oxo-2-thiomorpholin-4-ylethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide

The compound was prepared in a manner similar to that described inExample 18 and lyophilized from dioxane to give the product as anoff-white solid.

¹H NMR (DMSO, 400 MHz) δ 10.6 (1H, bs), 8.65 (1H, d, J=4.2 Hz), 7.94(1H, d, J=8.6 Hz), 7.8-7.6 (4H, m), 5.22 (2H, bs), 4.93 (2H, bd, J=5.1Hz), 3.86 (2H, bs), 3.8-3.6 (2H, bs), 3.57 (3H, s), 2.8 (2H, bs), 2.6(2H, bs) ppm.

MS calc'd for C₂₃H₂₃FN₄O₆S₂ 534 (M), found 534.9 (MH+) Low Res MSElectrospray

EXAMPLE 28

Oral Compositions

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of compound of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule. Encapsulated oral compositionscontaining any one of the compounds of Examples 2-27 can be similarlyprepared.

EXAMPLE 29

HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase

Assays for the strand transfer activity of integrase were conducted inaccordance with the method described in Example 193 of WO 02/30930 forrecombinant integrase. Representative compounds of the present inventionexhibit inhibition of strand transfer activity in this assay. Forexample, the compounds prepared in Examples 1-27 were tested in theintegrase assay and all were found to have IC₅₀'s less than 0.5micromolar.

Further description on conducting the assay using preassembled complexesis found in Wolfe, A. L. et al., J. Virol. 1996, 70: 1424-1432, Hazudaet al., J. Virol. 1997, 71: 7005-7011; Hazuda et al., Drug Design andDiscovery 1997, 15: 17-24; and Hazuda et al., Science 2000, 287:646-650.

EXAMPLE 30

Assay for Inhibition of HIV Replication

Assays for the inhibition of acute HIV infection of T-lymphoid cellswere conducted in accordance with Vacca, J. P. et al., (1994), Proc.Natl. Acad. Sci. USA 91, 4096. Representative compounds of the presentinvention exhibit inhibition of I-UV replication in this assay. Forexample, the compounds prepared in Examples 1-27 were tested in thepresent assay and all were found to have IC₉₅'s less than 5 micromolar.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, thepractice of the invention encompasses all of the usual variations,adaptations and/or modifications that come within the scope of thefollowing claims.

1. A compound of Formula (I):

wherein L is a linker connecting the carbon atom of the phenyl ring tothe nitrogen of the —NH-moiety, wherein L is (i) a single bond, (ii)—(C₁₋₆ alkyl)-, which is optionally substituted with—C(═O)N(R^(a)R^(b)), (iii) —(C₀₋₃ alkyl)-C═C—(C₁₋₃ alkyl)-, (iv) —(C₀₋₃alkyl)-C≡C—(C₁₋₃ alkyl)-, or (v) —(C₀₋₆ alkyl)-(C₃₋₆ cycloalkyl)-(C₀₋₆alkyl)-; R^(1a), R^(1b), and R^(1c) are each independently —H, halogen,—C₁₋₆ alkyl, or —C₁₋₆ haloalkyl; R^(2a) and R^(2b) are eachindependently: (1) —H, (2) —C₁₋₆ alkyl, optionally substituted with oneor more substituents each of which is independently halogen, —OH,—O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a), —S(O)_(n)R^(a),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),—N(R^(a))SO₂R^(b), or —N(R^(a))SO₂N(R^(a)R^(b)), (3) —C₁₋₆ alkylsubstituted with one substituent which is —C₃₋₈ cycloalkyl, aryl, orheteroaryl, wherein: (a) the cycloalkyl is optionally substituted withone or more substituents each of which is independently halogen, —OH,—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, or phenyl; (b) the aryl is an aromatic carbocyclicring or an aromatic carbocyclic fused ring system, wherein the aryl isoptionally substituted with one or more substituents each of which isindependently halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆alkyl,—C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂,—N(R^(a)R^(b)), —C₁₋₆ alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C₁₋₆alkyl-C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —C₁₋₆ alkyl-C(═O)R^(a),—CO₂R^(a), —C₁₋₆ alkyl-CO₂R^(a), —OCO₂R^(a), —C₁₋₆ alkyl-OCO₂R^(a),—S(O)_(n)R^(a), —C₁₋₆ alkyl-S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —C₁₋₆alkyl-SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b), —C₁₋₆ alkyl-N(R^(a))SO₂R^(b),—N(R^(a))C(═O)R^(b), —C₁₋₆ alkyl-N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),—C¹⁻⁶ alkyl-N(R^(a))CO²R^(b), —N(R^(a))SO₂N(R^(a)R^(b)), —C₁₋₆alkyl-N(R^(a))SO₂N(R^(a)R^(b)), phenyl, —C₁₋₆ alkyl-phenyl, —O-phenyl,—C₁₋₆ alkyl-O-phenyl, HetA, or —C₁₋₆ alkyl-HetA; wherein each HetA is a5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally fused with a benzene ring; and wherein each HetA isoptionally substituted with one or more substituents each of which isindependently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, oxo, or —CO₂R^(a); and (c) the heteroaryl is a 5- or6-membered heteraromatic ring containing from 1 to 4 heteroatoms or a 9-or 10-membered bicyclic heteroaromatic ring system containing from 1 to6 heteroatoms, wherein the heteroatoms in the heteroaryl areindependently selected from N, O and S; and wherein the heteroaryl isoptionally substituted with one or more substituents each of which isindependently halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —N(R^(a)R^(b)), —C₁₋₆alkyl-N(R^(a)), —C(═O)N(R^(a)R^(b)), —C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),—C(═O)R^(a), —C₁₋₆ alkyl-C(═O)R^(a), —CO₂R^(a), —C₁₋₆ alkyl-CO₂R^(a),—OCO₂R^(a), —C₁₋₆ alkyl-OCO₂R^(a), —S(O)_(n)R^(a), —C₁₋₆alkyl-S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —C₁₋₆ alkyl-SO₂N(R^(a)R^(b)),—N(R^(a))SO₂R^(b), —C₁₋₆ alkyl-N(R^(a))SO₂R^(b), —N(R^(a))C(═O)R_(b),—C₁₋₆ alkyl-N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —C₁₋₆alkyl-N(R^(a))CO₂R^(b), phenyl, —C₁₋₆ alkyl-phenyl, or oxo; (4) —O—C₁₋₆alkyl, optionally substituted with one or more substituents each ofwhich is independently halogen, —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,—S(O)_(n)R^(a), —N(R^(a))—CO₂R^(b), or —C(═O)N(R^(a)R^(b)), (5) —OH, (6)halo, (7) —NO₂, (8) —CN, (9) —C(═O)R^(a), (10) —CO₂R^(a), (11)—S(O)_(n)R^(a), (12) —SO₂N(R^(a)R^(b)), (13) —N(R^(a)R^(b)), (14)—C(═O)N(R^(a)R^(b)), (15) —N(R^(a))SO₂R^(b), (16) —OC(═O)N(R^(a)R^(b)),(17) —N(R^(a))C(═O)N(R^(a)R^(b)), (18) —N(R^(a))—C₁₋₆alkyl-C(═O)N(R^(a)R^(b)), (19) —N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),(20) —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), (21) —OCO₂R^(a), (22)—N(R^(a))—SO₂N(R^(a)R^(b)), (23) —N(R^(a))—SO₂—C₁₋₆ alkyl-N(R^(a)R^(b)),(24) —N(R^(a))C(═O)R^(b), (25) —N(R^(a))CO₂R^(b), (26) —S—C₁₋₆alkyl-C(═O)N(R^(a)R^(b)), or (27) —N(SO₂R^(a))—C₁₋₆alkyl-C(═O)N(R^(a)R^(b)); R³ is (1) —H, (2) —C₁₋₆ alkyl, optionallysubstituted with one or more substituents each of which is independentlyhalogen, —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂,—N(R^(a)R^(b)), C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),—N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),—N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),—N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a),—S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂N(R^(a)R^(b)),—N(R^(a))—SO₂—C₁₋₆ alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),—N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or -G-C₁₋₆alkyl-C(═O)N(R^(a)R^(b)) wherein G is O or S or N(SO₂R^(a)), with theproviso that none of the following substituents is attached to thecarbon in the —C₁₋₆ alkyl group that is attached to the ring nitrogen:—OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —NO₂, —N(R^(a)R^(b)),—OC(═O)N(R^(a)R^(b)), —N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),—N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —OCO₂R^(a),—N(R^(a))—SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂—C₁₋₆ alkyl-N(R^(a)R^(b)),—N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or -G-C₁₋₆alkyl-C(═O)N(R^(a)R^(b)) wherein G is O or N(SO₂R^(a)), (3) —C₁₋₆ alkylsubstituted with one of: (i) —R^(k), (ii) —S(O)_(n)—R^(k), (iii)—S(O)_(n)—C₁₋₆ alkyl-R^(k), (iv) —C(═O)—R^(k), (v) —C(═O)—C₁₋₆alkyl-R^(k), (vi) —C(═O)N(R^(a))—R^(k), or (vii) —C(═O)N(R^(a))—C₁₋₆alkyl-R^(k), (4) —C₂₋₆ alkyl substituted with one of: (i) —O—R^(k), (ii)—O—C₁₋₆ alkyl-R^(k), (iii) —N(R^(a))—R^(k), (iv) —N(R^(a))—C₁₋₆alkyl-R^(k), (v) —N(R^(a))C(═O)—R^(k), (vi) —N(R^(a))C(═O)—C₁₋₆alkyl-R^(k), with the proviso that the substituent is not attached tothe carbon in the —C₂₋₆ alkyl group that is attached to the ringnitrogen, (5) —S(O)_(n)R^(a), (6) —SO₂N(R^(a)R^(b)), (7) —C₂₋₆ alkenyl,optionally substituted with one substituent which is—C(═O)—N(R^(a)R^(b)) or —R^(k), (8) —C₂₋₅ alkynyl, optionallysubstituted with one substituent which is —CH₂N(R^(a)R^(b)), —CH₂OR^(a),or —R^(k), (9) —R^(k), (10) —S(O)_(n)—C₁₋₆ alkyl-R^(k), (11)—N(R^(a))C(═O)—R^(k), or (12) —N(R^(a))C(═O)—C₁₋₆ alkyl-R^(k); each ofR⁴ and R⁵ is independently (1) —H, (2) —C₁₋₆ alkyl, optionallysubstituted with one or more substituents each of which is independentlyhalogen, —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂,—N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),—N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),—N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),—N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a),—S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂N(R^(a)R^(b)),—N(R^(a))—SO₂—C₁₋₆ alkyl-N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),—N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), or -G-C₁₋₆alkyl-C(═O)N(R^(a)R^(b)) wherein G is O or S or N(SO₂R^(a)), (3)—SO₂N(R^(a)R^(b)), or (4) —C₁₋₆ alkyl-R^(m); each R^(a) and R^(b) isindependently —H, —C₁₋₆ alkyl, or —C₃₋₈ cycloalkyl; R^(k) is acarbocycle or a heterocycle; each R^(m) is independently a carbocycle ora heterocycle; each carbocycle is independently (i) a C₃ to C₈monocyclic, saturated or unsaturated ring, (ii) a C₇ to C₁₂ bicyclicring system, or (iii) a C₁₁ to C₁₆ tricyclic ring system, wherein eachring in (ii) or (iii) is independent of or fused to the other ring orrings and each ring is saturated or unsaturated; wherein the carbocycleis optionally substituted with one or more substituents each of which isindependently (1) halogen, (2) —OH, (3) —C₁₋₆ alkyl, optionallysubstituted with one or more substituents each of which is independently—OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a), —S(O)_(n)R^(a),—SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b), —N(R^(a))C(═O)R^(b),—N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), phenyl, —O-phenyl, or HetB, (4)—C₁₋₆ haloalkyl, (5) —O—C₁₋₆ alkyl, (6) —O—C₁₋₆ haloalkyl, (7) —CN, (8)—NO₂, (9) —N(R^(a)R^(b)), (10) —C(═O)N(R^(a)R^(b)), (11) —C(═O)R^(a),(12) —CO₂R^(a), (13) —OCO₂R^(a), (14) —S(O)_(n)R^(a), (15)—N(R^(a))SO₂R^(b), (16) —SO₂N(R^(a)R^(b)), (17) —N(R^(a))C(═O)R^(b),(18) —N(R^(a))CO₂R^(b), (19) phenyl, (20) —O-phenyl, or (21) HetB,wherein each HetB is independently a 5- or 6-membered heteroaromaticring containing from 1 to 4 heteroatoms independently selected from N, Oand S, wherein the heteroaromatic ring is optionally fused with abenzene ring; and wherein each HetB is optionally substituted with oneor more substituents each of which is independently —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo, or —CO₂R^(a); eachheterocycle is independently (i) a 4- to 8-membered, saturated orunsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ringsystem, or (iii) an 11 to 16-membered tricyclic ring system; whereineach ring in (ii) or (iii) is independent of or fused to the other ringor rings and each ring is saturated or unsaturated; the monocyclic ring,bicyclic ring system, or tricyclic ring system contains from 1 to 6heteroatoms independently selected from N, O and S; and wherein any oneor more of the nitrogen and sulfur heteroatoms is optionally oxidized,and any one or more of the nitrogen heteroatoms is optionallyquaternized; wherein the heterocycle is optionally substituted with oneor more substituents each of which is independently (1) halogen, (2)—OH, (3) —C₁₋₆ alkyl, optionally substituted with one or moresubstituents each of which is independently —OH, —O—C₁₋₆ alkyl, —CN,—NO₂, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a),—S(O)_(n)R^(a), —N(R^(a))SO₂R^(b), —SO₂N(R^(a)R^(b)),—N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), phenyl, —O-phenyl, or HetC, (4)—C₁₋₆ haloalkyl, (5) —O—C₁₋₆ alkyl, (6) —O—C₁₋₆ haloalkyl, (7) —CN, (8)—NO₂, (9) —N(R^(a)R^(b)), (10) —C(═O)N(R^(a)R^(b)), (11) —C(═O)R^(a),(12) —CO₂R^(a), (13) —OCO₂R^(a), (14) —S(O)_(n)R^(a), (15)—N(R^(a))SO₂R^(b), (16) —SO₂N(R^(a)R^(b)), (17) —N(R^(a))C(═O)R^(b),(18) —N(R^(a))CO₂R^(b), (19) phenyl, (20) —O-phenyl, (21) HetC, or (22)oxo; wherein each HetC is independently a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallyfused with a benzene ring; and wherein each HetC is optionallysubstituted with one or more substituents each of which is independently—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O-C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo, or—CO₂R^(a); and each n is independently an integer equal to 0, 1 or 2; ora pharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R^(1a) and R^(1c) are both —H; and R^(1b) is fluoro; ora pharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1, wherein R^(2a) and R^(2b) are each independently: (1) —H, (2)—C₁₋₄ alkyl, optionally substituted with 1 or 2 substituents each ofwhich is independently —OH, —O—C₁₋₄ alkyl, —O—CF₃, —CN, —NO₂,—N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —OCO₂R^(a),—S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),—N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b), (3) —CF₃, (4) —C₁₋₄ alkylsubstituted with one of —C₃₋₆ cycloalkyl, aryl, or heteroaryl, wherein:the cycloalkyl is optionally substituted with 1 or 2 substituents eachof which is independently fluoro, chloro, bromo, —OH, —C₁₋₄ alkyl,—(CH₂)₁₋₂—O—C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃, or phenyl; the arylis phenyl, naphthyl, anthryl, or phenanthryl; wherein the aryl isoptionally substituted with from 1 to 3 substituents each of which isindependently fluoro, chloro, bromo, —OH, —C₁₋₄ alkyl, —(CH₂)₁₋₂—O—C₁₋₄alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃, —CN, —NO₂, —N(R^(a)R^(b)), —C₁₋₄alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C₁₋₄alkyl-C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —C₁₋₄ alkyl-C(═O)R^(a),—CO₂R^(a), —C₁₋₄ alkyl-CO₂R^(a), —OCO₂R^(a), —C₁₋₄ alkyl-OCO₂R^(a),—S(O)_(n)R^(a), —C₁₋₄ alkyl-S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —C₁₋₄alkyl-SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b), —C₁₋₄ alkyl-N(R^(a))SO₂R^(b),—N(R^(a))C(═O)R^(b), —C₁₋₄ alkyl-N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),—C₁₋₄ alkyl-N(R^(a))CO₂R^(b), —N(R^(a))SO₂N(R^(a)R^(b)), —C₁₋₄alkyl-N(R^(a))SO₂N(R^(a)R^(b)), phenyl, —C₁₋₄ alkyl-phenyl, —O-phenyl,—C₁₋₄ alkyl-O-phenyl, HetA, or —C₁₋₄ alkyl-HetA; wherein each HetA is a5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally fused with a benzene ring; and wherein each HetA isoptionally substituted with from 1 to 4 substituents each of which isindependently —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃, oxo, or—CO₂R^(a); and the heteroaryl is a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; wherein the heteroaryl is optionally substituted with 1 or 2substituents each of which is independently fluoro, chloro, bromo, —OH,—C₁₋₄ alkyl, —(CH₂)₁₋₂—O—C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, —OCF₃,—N(R^(a)R^(b)), —C₁₋₄ alkyl-N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C₁₋₄alkyl-C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —C₁₋₄ alkyl-C(═O)R^(a),—CO₂R^(a), —C₁₋₄ alkyl-CO₂R^(a), —OCO₂R^(a), —C₁₋₄ alkyl-OCO₂R^(, —S(O))_(n)R^(a), —SO₂N(R^(a)R^(b)), —C₁₋₄ alkyl-S(O)_(n)R^(a),—SO₂N(R^(a)R^(b)), —N(R^(a))SO₂R^(b), —C₁₋₄ alkyl-N(R^(a))SO₂R^(b),—N(R^(a))C(═O)R^(b), —C₁₋₄ alkyl-N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),—C₁₋₄ alkyl-N(R^(a))CO₂R^(b), phenyl, —C₁₋₄ alkyl-phenyl, or oxo; (5)—O—C₁₋₆ alkyl, optionally substituted with 1 or 2 substituents each ofwhich is independently —OH, —O—C₁₋₄ alkyl, —OCF₃, 'S(O)_(n)R^(a), or-NH-CO2R^(a), or —C(═O)N(R^(a)R^(b)), (6) —OCF₃, (7) —OH, (8) fluoro,chloro, or bromo, (9) —NO₂, (10) —CN, (11) —C(═O)R^(a), (12) —CO₂R^(a),(13) —S(O)_(n)R^(a), (14) —SO₂N(R^(a)R^(b)), (15) —N(R^(a)R^(b)), (16)—C(═O)N(R^(a)R^(b)), (17) —N(R^(a))SO₂R^(b), or (18)—N(R^(a))C(═O)R^(b); or a pharmaceutically acceptable salt thereof. 4.The compound according to claim 3, wherein R^(2a) and R^(2b) are eachindependently: (1) —H, (2) —C₁₋₄ alkyl, (3) —C₁₋₂ alkyl substituted withone substituent which is —OH, OCH₃, —CN, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), —SR^(a), —SO₂R^(a),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b), or—N(R^(a))SO₂R^(b), (4) —CF₃, (5) —CH₂-cyclopropyl, (6) —CH₂-phenyl,wherein the phenyl is optionally substituted with from 1 to 3substituents each of which is independently fluoro, chloro, bromo, —C₁₋₄alkyl, —CH₂OCH₃, —CF₃, —O—C₁₋₄ alkyl, —OCF₃, —CN, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a), or —S(O)_(n)R^(a); (7)—CH₂-heteroaryl, wherein the heteroaryl is pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, thienyl, furanyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, or thiadiazolyl; and wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents each of which is independentlyfluoro, chloro, bromo, —C₁₋₄ alkyl, —O—C₁₋₄ alkyl, or oxo, (8) —O—C₁₋₄alkyl, (9) —OCF₃, (10) —OH (11) fluoro, chloro, or bromo, (12) —NO₂,(13) —CN, (14) —C(═O)R^(a), (15) —CO₂R^(a), (16) —S(O)_(n)R^(a), (17)—SO₂N(R^(a)R^(b)), (18) —N(R^(a)R^(b)), (19) —C(═O)N(R^(a)R^(b)), (20)—N(R^(a))SO₂R^(b), or (21) —N(R^(a))C(═O)R^(b); each R^(a) and R^(b) isindependently —H or —C₁₋₄ alkyl; or a pharmaceutically acceptable saltthereof.
 5. The compound according to claim 4, wherein R^(2a) and R^(2b)are each independently: (1) —H, (2) —C₁₋₄ alkyl, (3) —CF₃, (4) fluoro,chloro, or bromo, (5) —SO₂—C₁₋₄ alkyl, (6) —S—C₁₋₄ alkyl, (7)—SO₂N(—C₁₋₄ alkyl)₂, (8) —C(═O)N(—C₁₋₄ alkyl)₂, (9) —NHSO₂—C₁₋₄ alkyl,(10) —N(—C₁₋₄ alkyl)SO₂—C₁₋₄ alkyl, (11) —NHC(═O)—C₁₋₄ alkyl, (12)—N(—C₁₋₄ alkyl)C(═O)—C₁₋₄ alkyl, or (13) —C(═O)NH(—C₁₋₄ alkyl); or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 5, wherein one of R^(2a) and R^(2b) is —H, and the other of R^(2a)and R^(2b) is as defined in claim 5; or a pharmaceutically acceptablesalt thereof.
 7. The compound according to claim 6, wherein one ofR^(2a) and R^(2b) is —H, and the other of R^(2a) and R^(2b) is: (1) —H,(2) —SO₂CH₃, (3) —SO₂CH₂CH₃, (4) —S—CH₃, (5) —S—CH₂CH₃, or (6)—C(═O)NH(CH₃); or a pharmaceutically acceptable salt thereof.
 8. Thecompound according to claim 1, wherein R³ is: (1) —H, (2) —C₁₋₄ alkyl,optionally substituted with one substituent which is —O—C₁₋₄ alkyl, —CN,—N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)),—N(R^(a))C(═O)N(R^(a)R^(b)), —N(R^(a))C(═O)CH₂N(R^(a)R^(b)),—N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(a),—S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), —N(R^(a))CO₂R^(b),—N(R^(a))—SO₂N(R^(a)R^(b)), —N(R^(a))—SO₂CH₂N(R^(a)R^(b)), or—N(R^(a))SO₂R^(b), with the proviso that none of the followingsubstituents is attached to the carbon in the —C₁₋₄ alkyl group that isattached to the ring nitrogen: —O—C₁₋₄ alkyl, —N(R^(a)R^(b)),—OC(═O)N(R^(a)R^(b)), —N(R^(a))C(═O)N(R^(a)R^(b)),—N(R^(a))—C(═O)—CH₂N(R^(a)R^(b)), —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),—N(R^(a))CO₂R^(b), —N(R^(a))—SO₂N(R^(a)R^(b)),—N(R^(a))—SO₂—CH₂N(R^(a)R^(b)), or —N(R^(a))SO₂R^(b), (3) —C₁₋₄alkyl-R^(k), (4) —C₁₋₄ alkyl-C(═O)—R^(k), or (5) —CH₂₋₄alkyl-N(R^(a))-C(═O)—R^(k), with the proviso that the substituent is notattached to the carbon in the —C₂₋₄ alkyl group that is attached to thering nitrogen; wherein R^(k) is: (i) phenyl, which is optionallysubstituted with from 1 to 3 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄haloalkyl, (ii) a 5- or 6-membered saturated heterocyclic ringcontaining from 1 to 4 heteratoms selected from N, O and S, wherein thesaturated heterocyclic ring is optionally substituted with from 1 to 3substituents each of which is independently —C₁₋₄ alkyl or oxo, or (iii)a 5- or 6-membered heteroaromatic ring containing from 1 to 4heteroatoms independently selected from N, O and S, wherein theheteroaromatic ring is optionally substituted with from 1 to 3substituents each of which is independently halogen, —C₁₋₄ alkyl, or—O—C₁₋₄ alkyl; or a pharmaceutically acceptable salt thereof.
 9. Thecompound according to claim 8, wherein R³ is: (1) —H, (2) —C₁₋₄ alkyl,(3) —(CH₂)₂₋₃—O—C₁₋₄ alkyl, (4) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)₂, (5)—(CH₂)₁₋₃—C(═O)N(—C₁₋₄ alkyl)₂, (6) —(CH₂)₂₋₃—OC(═O)N(—C₁₋₄ alkyl)₂, (7)—(CH₂)₂₋₃—N(—C₁₋₄ alkyl)C(═O)N(—C₁₋₄ alkyl)₂, (8) —(CH₂)₂₋₃—N(—C₁₋₄alkyl)C(═O)—CH₂N(—C₁₋₄ alkyl)₂, (9) —(CH₂)₂₋₃—N(—C₁₋₄alkyl)C(═O)—C(═O)N(—C₁₋₄ alkyl)₂, (10) —(CH₂)₁₋₃—CO₂—C₁₋₄ alkyl, (11)—(CH₂)₁₋₃—S(O)_(n)—C₁₋₄ alkyl, (12) —(CH₂)₁₋₃—SO₂N(—C₁₋₄ alkyl)₂, (13)—(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-CO₂—C₁₋₄ alkyl, (14) —(CH₂)₂₋₃—N(—C₁₋₄alkyl)-SO₂N('C₁₋₄ alkyl)₂, (15) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-SO₂CH₂N(—C₁₋₄alkyl)₂, (16) —(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-SO₂—C₁₋₄ alkyl, (17)—(CH₂)₁₋₃—R^(k), (18) —(CH₂)₁₋₃—C(═O)—R^(k), or (19) —(CH₂)₂₋₃—N(—C₁₋₄alkyl)-C(═O)—R^(k); or a pharmaceutically acceptable salt thereof. 10.The compound according to claim 1, wherein each of R⁴ and R⁵ isindependently: (1) —H, (2) —C₁₋₄ alkyl, optionally substituted with onesubstituent which is —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)),—C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)), or—N(R^(a))SO₂R^(b), or (3) —C₁₋₄ alkyl-R^(m), wherein each R^(m) isindependently: (i) phenyl, which is optionally substituted with from 1to 3 substituents each of which is independently halogen, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl, (ii) a 5- or6-membered saturated heterocyclic ring containing from 1 to 4 heteratomsselected from N, O and S, wherein the saturated heterocyclic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl or oxo, or (iii) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 3 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl; or a pharmaceutically acceptablesalt thereof.
 11. The compound according to claim 10, wherein R⁴ and R⁵are both —H; or a pharmaceutically acceptable salt thereof.
 12. Thecompound according to claim 1, wherein L is CH₂; or a pharmaceuticallyacceptable salt thereof.
 13. A compound of Formula (II):

wherein: R^(1b) is —H, fluoro, chloro, bromo, —C₁₋₄ alkyl, or —CF₃;R^(2a) is: (1) —H, (2) —C₁₋₄ alkyl, (3) —CF₃, (4) fluoro, chloro, orbromo, (5) —SO₂—C₁₋₄ alkyl, (6) —S—C₁₋₄ alkyl, (7) —SO₂N(R^(a)R^(b)),(8) —N(R^(a))SO₂—C₁₋₄ alkyl, or (9) —C(═O)N(R^(a)R^(b)); R³ is: (1) —H,(2) —C₁₋₄ alkyl, optionally substituted with one substituent which is—O—C₁₋₄ alkyl, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)),—OC(═O)N(R^(a)R^(b)), —N(R^(a))C(═O)N(R^(a)R^(b)),—N(R^(a))C(═O)CH₂N(R^(a)R^(b)), —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),—C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), —SO₂N(R^(a)R^(b)),—N(R^(a))CO₂R^(b), —N(R^(a))—SO₂N(R^(a)R^(b)),—N(R^(a))—SO₂CH₂N(R^(a)R^(b)), or —N(R^(a))SO₂R^(b), with the provisothat none of the following substituents is attached to the carbon in the-C1 4 alkyl group that is attached to the ring nitrogen: —O—C₁₋₄ alkyl,—N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), —N(R^(a))C(═O)N(R^(a)R^(b)),—N(R^(a))—C(═O)—CH₂N(R^(a)R^(b)), —N(R^(a))C(═O)—C(═O)N(R^(a)R^(b)),—N(R^(a))CO₂R^(b), —N(R^(a))—SO₂N(R^(a)R^(b)),—N(R^(a))—SO₂—CH₂N(R^(a)R^(b)), or —N(R^(a))SO₂R^(b), (3) —C₁₋₄alkyl-R^(k), (4) —C₁₋₄ alkyl-C(═O)—R^(k), or (5) —C₂₋₄alkyl-N(R^(a))—C(═O)—R^(k), with the proviso that the substituent is notattached to the carbon in the —C₂₋₄ alkyl group that is attached to thering nitrogen; wherein R^(k) is: (i) phenyl, which is optionallysubstituted with from 1 to 3 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄haloalkyl, (ii) a 5- or 6-membered saturated heterocyclic ringcontaining from 1 to 4 heteratoms selected from N, O and S, wherein thesaturated heterocyclic ring is optionally substituted with from 1 to 3substituents each of which is independently —C₁₋₄ alkyl or oxo, or (iii)a 5- or 6-membered heteroaromatic ring containing from 1 to 4heteroatoms independently selected from N, O and S, wherein theheteroaromatic ring is optionally substituted with from 1 to 3substituents each of which is independently halogen, —C₁₋₄ alkyl, or—O—C₁₋₄ alkyl; each R^(a) and R^(b) is independently —H or —C₁₋₄ alkyl;and n is an integer equal to zero, 1 or 2; or a pharmaceuticallyacceptable salt thereof.
 14. The compound according to claim 13,wherein: R^(1b) is fluoro, chloro, bromo, methyl, or ethyl; R^(2a) is:(1) —H, (2) methyl or ethyl, (3) fluoro, (4) —SO₂—C₁₋₄ alkyl, (5)—S—C₁₋₄ alkyl, (6) —SO₂N(—C₁₋₄ alkyl)₂, (7) —NHSO₂—C₁₋₄ alkyl, (8)—N(—C₁₋₄ alkyl)SO₂—C₁₋₄ alkyl, or (9) —C(═O)NH(—C₁₋₄ alkyl); R³ is: (1)—H, (2) —C₁₋₄ alkyl, (3) —(CH₂)₂₋₃—O—C₁₋₄ alkyl, (4) —(CH₂)₂₋₃—N(—C₁₋₄alkyl)₂, (5) —(CH₂)₁₋₃—C(═O)N(—C₁₋₄ alkyl)₂, (6) —(CH₂)₂₋₃—N(—C₁₋₄alkyl)C(═O)N(—C₁₋₄ alkyl)₂, (7) —(CH₂)₂₋₃—N(—C₁₋₄alkyl)C(═O)—C(═O)N(—C₁₋₄ alkyl)₂, (8) —(CH₂)₁₋₃—CO₂—C₁₋₄ alkyl, (9)—(CH₂)₁₋₃—S(O)_(n)—C₁₋₄ alkyl, (10) —(CH₂)₁₋₃—SO₂N(—C₁₋₄ alkyl)₂, (11)—(CH₂)₂₋₃—N(—C₁₋₄ alkyl)-SO₂N(—C₁₋₄ alkyl)₂, (12) —(CH₂)₂₋₃—N(—C₁₋₄alkyl)-SO₂—C₁₋₄ alkyl, (13) —(CH₂)₁₋₃—R^(k), (14) —(CH₂)₁₋₃—C(═O)—R^(k),or (15) —(CH₂)₂₋₃—N(R^(a))—C(═O)—R^(k); or a pharmaceutically acceptablesalt thereof.
 15. The compound according to claim 14, wherein: R^(1b) isfluoro; R^(2a) is: (1) —H, (2) fluoro, (3) —SO₂—C₁₋₄ alkyl, (4) —S—C₁₋₄alkyl, (5) —SO₂N(—C₁₋₄ alkyl)₂, (6) —NHSO₂—C₁₋₄ alkyl, (7) —N(—C₁₋₄alkyl)SO₂—C₁₋₄ alkyl, or (8) —C(═O)NH(—C₁₋₄ alkyl); R³ is: (1) —H, (2)—C₁₋₄ alkyl, (3) —(CH₂)₂₋₃—O—C₁₋₄ alkyl, (4) —(CH₂)₂₋₃—N(—C₁₋₂ alkyl)₂,(5) —(CH₂)₁₋₃—C(═O)N(—C₁₋₂ alkyl)₂, (6) —(CH₂)₂₋₃—N(—C₁₋₂alkyl)C(═O)N(—C₁₋₂ alkyl)₂, (7) —(CH₂)₂₋₃—N(—C₁₋₂alkyl)C(═O)—C(═O)N(—C₁₋₂ alkyl)₂, (8) —(CH₂)₁₋₃—S(O)_(n)—C₁₋₂ alkyl, (9)—(CH₂)₁₋₃—SO₂N(—C₁₋₂ alkyl)₂, (10) —(CH₂)₂₋₃—N(—C₁₋₂ alkyl)-SO₂N(—C₁₋₂alkyl)₂, (11) —(CH₂)₂₋₃—N(—C₁₋₂ alkyl)-SO₂—C₁₋₂ alkyl, (12)—(CH₂)₁₋₃—R^(k), or (13) —(CH₂)₁₋₃—C(═O)—R^(k); or a pharmaceuticallyacceptable salt thereof.
 16. The compound according to claim 15, whereinR^(k) is: (i) phenyl which is optionally substituted with from 1 to 3substituents each of which is independently fluoro, chloro, bromo, —C₁₋₄alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃; (ii) a saturated heterocyclic ringselected from the group consisting of piperidinyl, piperazinyl,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,isothiazolidinyl, tetrahydrothienyl, tetrahydrofuryl, thiazinanyl,thiadiazinanyl, and dioxanyl; wherein the saturated heterocyclic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl or oxo; or (iii) a heteroaromatic ringselected from the group consisting of pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, thienyl, furanyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, and thiadiazolyl; wherein the heteroaromatic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently halogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl; or apharmaceutically acceptable salt thereof.
 17. A compound selected fromthe group consisting of:

and pharmaceutically acceptable salts thereof.
 18. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to either claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 19. A method ofinhibiting HIV integrase in a subject in need thereof which comprisesadministering to the subject a therapeutically effective amount of thecompound according to either claim 1, or a pharmaceutically acceptablesalt thereof.
 20. A method for preventing or treating infection by HIVor for preventing, treating or delaying the onset of AIDS in a subjectin need thereof which comprises administering to the subject atherapeutically effective amount of the compound according to eitherclaim 1, or a pharmaceutically acceptable salt thereof. 21-23.(canceled)